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1.  Acute myeloid leukaemia with t(8;21) associated with “occult” mastocytosis. Report of an unusual case and review of the literature 
Journal of Clinical Pathology  2004;57(3):324-328.
Approximately 20% of patients with systemic mastocytosis (SM) have an associated haematological, clonal, non-mast cell lineage disease, and most exhibit an associated myelogenous neoplasm. This report describes a 48 year old man with acute myeloid leukaemia (AML) and a type t(8;21) cytogenetic abnormality. Associated bone marrow mastocytosis (a defined subtype of SM) was only detected after successful polychemotherapy in the state of bone marrow aplasia, and persisted after complete remission of AML. The diagnosis of mastocytosis was based on the demonstration of a multifocal dense mastocytic infiltrate. The atypical mast cells showed prominent spindling and an aberrant immunophenotype, with coexpression of tryptase, chymase, KIT, and CD25—which is expressed only on neoplastic (not normal) mast cells. In addition, the transforming somatic mutation D816V of the c-kit gene was detected. Re-examination of the pretherapeutic (initial) bone marrow revealed a slight diffuse increase in partially spindle shaped mast cells also exhibiting an abnormal immunophenotype, with CD25 expression, although compact mastocytic infiltrates were not detected. Because the D816V mutation was detected in the initial bone marrow specimen, strict application of three minor diagnostic criteria (spindling, CD25, D816V) enabled a diagnosis of SM-AML to be confirmed retrospectively in the initial bone marrow tissue.
doi:10.1136/jcp.2003.012864
PMCID: PMC1770248  PMID: 14990611
mastocytosis; bone marrow; CD25; acute myeloid leukaemia; mast cell tryptase; occult; mastocytosis; c-kit mutation
2.  Prognosis and Therapy When Acute Promyelocytic Leukemia and Other “Good Risk” Acute Myeloid Leukemias Occur as a Therapy-Related Myeloid Neoplasm 
Treatment for a pre-existing condition using chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities may lead to the devastating complication of therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML), collectively known as therapy-related myeloid neoplasm (t-MN). This disorder arises as a direct consequence of mutational events induced by the primary treatment. The outcomes for these patients have been historically poor compared to people who develop AML de novo. Currently comprising 10–20% of all cases of AML, t-MN is relatively resistant to conventional leukemia therapies, and is associated with s ort survival times. Median life expectancy from diagnosis is about 8–10 months in most series. Although the spectrum of cytogenetic abnormalities in t-AML is similar to AML de novo, the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-MN. Two distinct groups of patients with t-MN have been described. The more common subtype, seen in about 75% of patients, typically occurs 5–7 years after first exposure to alkylating agents or radiation, is often preceded by a myelodysplastic syndrome (MDS), and is frequently accompanied by clonal cytogenetic abnormalities such as the loss of all or part of chromosomes 5 or 7. Mutations of the P53 tumor suppressor gene are also common. The risk is related to total cumulative exposure over time to alkylating agents. In contrast, among individuals who develop t-AML after treatment with topoisomerase II inhibitors, the latency period to the development of t-AML is often only 1–3 years, antecedent MDS is rare, and gene rearrangements involving MLL at 11q23 or RUNX1/AML1 at 21q22 are common. It is now well recognized that APL and other subtypes of AML with balanced translocations sometimes occur as therapy-related myeloid neoplasms (t-MN) in patients who have previously received cytotoxic therapy or ionizing radiation therapy (RT). The most of this review will focus on these “good risk” leukemias, i.e. those with APL or inv(16)/t(16;16) or t(8;21).
doi:10.4084/MJHID.2011.032
PMCID: PMC3152454  PMID: 21869918
3.  Hematopoietic Stem Cell Expansion and Distinct Myeloid Developmental Abnormalities in a Murine Model of the AML1-ETO Translocation 
Molecular and Cellular Biology  2002;22(15):5506-5517.
The t(8;21)(q22;q22) translocation, which fuses the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO), is one of the most frequent cytogenetic abnormalities associated with acute myelogenous leukemia (AML). It is seen in approximately 12 to 15% of AML cases and is present in about 40% of AML cases with a French-American-British classified M2 phenotype. We have generated a murine model of the t(8;21) translocation by retroviral expression of AML1-ETO in purified hematopoietic stem cells (HSC). Animals reconstituted with AML1-ETO-expressing cells recapitulate the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21) translocation. Primitive myeloblasts were increased to approximately 10% of bone marrow by 10 months posttransplant. Consistent with this observation was a 50-fold increase in myeloid colony-forming cells in vitro. Accumulation of late-stage metamyelocytes was also observed in bone marrow along with an increase in immature eosinophilic myelocytes that showed abnormal basophilic granulation. HSC numbers in the bone marrow of 10-month-posttransplant animals were 29-fold greater than in transplant-matched control mice, suggesting that AML1-ETO expression overrides the normal genetic control of HSC pool size. In summary, AMLI-ETO-expressing animals recapitulate many (and perhaps all) of the developmental abnormalities seen in human patients with the t(8;21) translocation, although the animals do not develop leukemia or disseminated disease in peripheral tissues like the liver or spleen. This suggests that the principal contribution of AML1-ETO to acute myeloid leukemia is the inhibition of multiple developmental pathways.
doi:10.1128/MCB.22.15.5506-5517.2002
PMCID: PMC133929  PMID: 12101243
4.  Recurrence of a t(8;21)-Positive Acute Myeloid Leukemia in the Form of a Granulocytic Sarcoma Involving Cranial Bones: A Diagnostic and Therapeutic Challenge 
Case Reports in Hematology  2013;2013:245395.
Granulocytic sarcoma (GS) is a rare extramedullary solid tumor defined as an accumulation of myeloblasts or immature myeloid cells. It can cooccur with or precede the acute myeloid leukemia (AML) as well as following treated AML. The incidence of GS in AML patients is 3–8% but it significantly rises in M2 FAB subtype AML. This variety of AML harbors t(8;21) in up to 20–25% of cases (especially in children and black ones of African origin) and, at a molecular level, it is characterized by the generation of a fusion gene known as RUNX1-RUNX1T1. Approximately 10% of M2 AML patients will develop GS, as a consequence, the t(8;21) and the relative transcript represent the most common cytogenetic and molecular abnormalities in GS. FLT3-ITD mutation was rarely described in AML patients presenting with GS. FLT3 ITD is generally strongly associated with poor prognosis in AML, and is rarely reported in patients with t(8;21). GS presentation is extremely variable depending on organs involved; in general, cranial bones and sinus are very rarely affected sites. We report a rare case of GS occurring as a recurrence of a previously treated t(8;21), FLT3-ITD positive AML, involving mastoid bones and paravertebral tissues.
doi:10.1155/2013/245395
PMCID: PMC3787645  PMID: 24109526
5.  A Case of Systemic Mastocytosis Associated with Acute Myeloid Leukemia Terminating as Aleukemic Mast Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation 
Annals of Laboratory Medicine  2013;33(2):125-129.
In up to 40% of systemic mastocytosis (SM) cases, an associated clonal hematological non-mast cell lineage disease such as AML is diagnosed before, simultaneously with, or after the diagnosis of SM. A 40-yr-old man was diagnosed with AML with t(8;21)(q22;q22). Mast cells were not noted at diagnosis, but appeared as immature forms at relapse. After allogeneic hematopoietic stem cell transplantation (HSCT), leukemic myeloblasts were not observed; however, neoplastic metachromatic blasts strikingly proliferated during the state of bone marrow aplasia, and finally, aleukemic mast cell leukemia developed. As the disease progressed, we observed serial morphologic changes from immature mast cells with myeloblasts to only metachromatic blasts and atypical mast cells as mast cell leukemia; FISH analysis showed that the neoplastic mast cells originated from the same clone as the leukemic myeloblasts of AML.
doi:10.3343/alm.2013.33.2.125
PMCID: PMC3589638  PMID: 23483057
Systemic mastocytosis; Acute myeloid leukemia; Aleukemic mast cell leukemia; Allogeneic hematopoietic stem cell transplantation
6.  A Multicenter Experience from Lebanon in Childhood and Adolescent Acute Myeloid Leukemia: High rate of Early Death in Childhood Acute Promyelocytic Leukemia 
Background
Acute myeloid leukemia (AML) is a disease with marked heterogeneity. Despite major improvement in outcome, it remains a life-threatening malignancy. Demographic and clinical data on pediatric AML is lacking among the Lebanese population.
Purpose
We aimed to identify clinical, molecular and outcome data in children with AML in Lebanon.
Methods
A retrospective chart review of children with AML diagnosed in three Lebanese hospitals during the past 8 years was conducted.
Results
From May 2002 through March 2010, we identified 24 children with AML in Saint George Hospital University Medical Center, University Medical Center Rizk Hospital, and Abou-Jaoude Hospital. Males and females were equally represented; median age at diagnosis was 9 years (range 1–24) and median WBC at diagnosis was 31 × 109/L (range: 2.1–376 × 109/L). Twenty five percent of patients (6 out of 24) had acute promyelocytic leukemia (APL). Karyotype was normal in 33% of patients; t(8;21), inv (16), t(8;9), t(7;11), t(9;11), complex chromosomal abnormality, monosomy 7 and trisomy 8 were the most common cytogenetic abnormalities encountered. Patients were treated on different European and North American protocols. Twelve patients (50%) achieved morphologic CR after cycle 1, 6 of them (50%) had bone marrow relapse within 11 months from diagnosis. Nine patients underwent allogeneic stem cell transplant, and 3 of them are alive at 5 years post-transplant. Early death rate was 16.6% of patients, mainly those with APL and a presenting WBC > 10 × 109/L. Fifty per cent of APL patients had an early death due to DIC despite starting ATRA therapy. Overall, median survival for AML patients who died from disease progression was 25.8 months (range: 1–60 months). Overall disease-free survival was 30.4%. Patients < 10 years of age had a 50% survival rate compared to 0% in patients > 10 years.
Conclusions
Our report highlights the needs in Lebanon for better supportive care of children with APL, including faster ATRA administration and, aggressive transfusions, easy access to stem cell transplant for high-risk AML patients and the need for a national homogenous treatment strategy for children with AML.
doi:10.4084/MJHID.2015.012
PMCID: PMC4283923  PMID: 25574371
7.  Profile of sapacitabine: potential for the treatment of newly diagnosed acute myeloid leukemia in elderly patients 
Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder that affects approximately 14,000 persons each year in the US. AML occurs at all ages but the incidence increases with age with the median age at diagnosis being 67 years. Advances in the treatment of AML over the past decades have led to improved survival, albeit mostly in younger patients. The prognosis of older patients with this disease over the same time span has not changed much and remains dismal. This review focuses on the epidemiology and characteristics of AML in elderly patients, the rationale for treating elderly AML patients, and the currently available and potential future treatment options such as sapacitabine. Elderly AML patients treated with intensive chemotherapy have a higher mortality rate, and a lower rate of complete remission and overall survival when compared to the younger population. This is due to both the different biology of the disease and the number of patient-specific factors. However, elderly AML patients treated with aggressive chemotherapy can achieve durable remissions, which offer prolonged survival and improved quality of life. Recent data also indicates that elderly AML patients deemed unfit for intensive chemotherapy benefit from leukemia-specific attenuated dose chemotherapy compared to supportive care alone. This has led to renewed interest to look for anti-leukemic therapies designed specifically for older patients. Sapacitabine, a novel oral nucleoside analog, promises good efficacy, favorable toxicity profile, and ease of administration; all of which makes it very appealing. Results from pre-clinical and clinical studies have been very encouraging and sapacitabine is currently being evaluated in a Phase III study, of which the results are eagerly awaited.
doi:10.2147/CIA.S39558
PMCID: PMC4018315  PMID: 24851045
AML; elderly; management; sapacitabine
8.  Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: a systematic review and meta-analysis of prospective clinical trials 
Context
The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (alloSCT) for poor-risk but not for good-risk AML. AlloSCT, autologous transplant and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML. We undertook a systematic review and meta-analysis of prospective trials evaluating alloSCT versus non-alloSCT therapies for AML-CR1.
Objective
To quantify relapse-free survival (RFS) and overall survival (OS) benefit of alloSCT for AML in CR1. In subgroup analyses, RFS and OS benefit of alloSCT was determined for good-, intermediate- and poor-risk AML.
Methods
Combining the search terms: ‘allogeneic’; ‘acut*’ and ‘leukem*/leukaem*/leucem*/leucaem*/aml’; ‘myelo*’ or ‘nonlympho*’, we searched the PubMed, Embase and Cochrane Registry of Controlled Trials databases in March 2009. 1712 articles were accessed.
Study Selection
Prospective trials assigning adult AML-CR1 patients to alloSCT versus non-alloSCT treatment(s) based on donor availability, and reporting RFS and/or OS outcomes on intent-to-treat, donor versus no-donor basis were identified.
Data Extraction
Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HR) (with 95% CI) were determined.
Data Synthesis
24 trials and 6,007 patients were analyzed. Inter-study heterogeneity was not significant. Fixed effects meta-analysis was performed. HR of relapse or death with alloSCT for AML-CR1 was 0.80 (0.74–0.86). Significant RFS benefit of alloSCT was documented for poor-risk (HR 0.69 (0.57–0.84)) and intermediate-risk AML (HR 0.76 (0.68–0.85)); but not for good-risk AML (HR 1.06 (0.80–1.42)). HR of death with alloSCT for AML-CR1 was 0.90 (0.82–0.97). Significant OS benefit of alloSCT was documented for poor-risk (HR 0.73 (0.59–0.90)) and intermediate-risk AML (HR 0.83 (0.74–0.93)); but not for good-risk AML (HR 1.07 (0.83–1.38)).
Conclusion
AlloSCT has significant RFS and OS benefit for intermediate- and for poor-risk AML, but not for good-risk AML in CR1.
doi:10.1001/jama.2009.813
PMCID: PMC3163846  PMID: 19509382
acute myeloid leukemia; allogeneic transplantation; meta-analysis
9.  Acute Myeloid Leukemia with the t(8;21) Translocation: Clinical Consequences and Biological Implications 
The t(8;21) abnormality occurs in a minority of acute myeloid leukemia (AML) patients. The translocation results in an in-frame fusion of two genes, resulting in a fusion protein of one N-terminal domain from the AML1 gene and four C-terminal domains from the ETO gene. This protein has multiple effects on the regulation of the proliferation, the differentiation, and the viability of leukemic cells. The translocation can be detected as the only genetic abnormality or as part of more complex abnormalities. If t(8;21) is detected in a patient with bone marrow pathology, the diagnosis AML can be made based on this abnormality alone. t(8;21) is usually associated with a good prognosis. Whether the detection of the fusion gene can be used for evaluation of minimal residual disease and risk of leukemia relapse remains to be clarified. To conclude, detection of t(8;21) is essential for optimal handling of these patients as it has both diagnostic, prognostic, and therapeutic implications.
doi:10.1155/2011/104631
PMCID: PMC3100545  PMID: 21629739
10.  Modeling Interactions Between Leukemia-Specific Chromosomal Changes, Somatic Mutations, and Gene Expression Patterns During Progression of Core-Binding Factor Leukemias 
Genes, chromosomes & cancer  2010;49(2):182-191.
In cancer genomes, changes observed during tumor progression can be difficult to separate from non-specific accumulation of cytogenetic changes due to cancer-associated genetic instability. We studied genetic changes occurring over time in cancers presenting with a relatively simple karyotype, namely two related core-binding factor (CBF) acute myeloid leukemias (AMLs), to assess how specific chromosomal changes are selected based on tumor subtype and acquired somatic mutations. Expression profiles for DNA replication/repair genes and the mutation status of KRAS, NRAS, FLT3, and KIT were compared with the karyotypic changes at diagnosis and relapse(s) in 94 cases of inv(16)(p13.1q22)-AML and 82 cases of t(8;21)(q22;q22)-AML. The majority of both AML types demonstrated a simple aneuploid pattern of cytogenetic progression, with highly distinctive patterns of chromosome copy number changes, such as +22 and +13 exclusively in inv(16)-AML and –Y and –X in t(8;21)-AML. Selection of certain cytogenetic changes correlated with particular somatic mutations, such as +8 with RAS mutation, and absence of kinase pathway mutations in t(8;21)-AML with localized deletions at chromosome band 9q22. Alterations in transcript levels of mitotic spindle kinases such as CHEK1, AURKA, and AURKB were associated with the aneuploid progression pattern, particularly in t(8;21) cases. Despite the similarity in the initiating genetics of the two CBF AML types, highly tumor-specific patterns of limited aneuploidy are noted that persist and continue to accumulate at relapse. Thus, activation of genetic instability, possibly through mitotic spindle dysregulation, leads rapidly to selection of advantageous single chromosome aneuploidy.
doi:10.1002/gcc.20732
PMCID: PMC4161977  PMID: 19908318
11.  Minimal Residual Disease-Directed Therapy for Childhood Acute Myeloid Leukemia: Results of the AML02 Multicenter Trial 
The lancet oncology  2010;11(6):543-552.
Summary
Background
We sought to improve outcome of childhood acute myeloid leukemia (AML) by applying risk-directed therapy based on the genetic abnormalities of the leukemic cells and measurements of minimal residual disease (MRD) as determined by flow cytometry during treatment.
Methods
From October 13, 2002 to June 19, 2008, 232 patients with de novo AML (n=206), therapy- or myelodysplasia-related AML (n=12), or mixed-lineage leukemia (n=14) were enrolled at eight centers. Block, nonblinded randomization, stratified by cytogenetic or morphologic subtype, assigned patients to high-dose (18 g/m2, n=113) or low-dose (2 g/m2, n=117) cytarabine (A), given together with daunorubicin (D) and etoposide (E) (Induction I); achievement of MRD negative status was the primary endpoint. Induction II consisted of ADE with or without gemtuzumab ozogamicin (GO); consolidation therapy included three additional courses of chemotherapy or hematopoietic stem cell transplantation (HSCT). Levels of MRD were used to allocate GO and determine the timing of Induction II; both MRD and genetic abnormalities at diagnosis were used to determine final risk classification. Low-risk patients (n=68) received 5 courses of chemotherapy, whereas high-risk patients (n=79), as well as standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (performed in 48 high and 8 standard-risk patients). All randomized patients (n=230) were analyzed for the primary endpoint. The other analyses were limited to the 216 patients with AML, excluding mixed-lineage leukemia. This trial, closed to accrual, is registered with ClinicalTrial.gov, number NCT00136084.
Findings
The complete remission rates were 80% (173 of the 216) after Induction I and 94% (203 of 216) after Induction II. Induction failures included two toxic deaths and 10 cases of resistant leukemia. The introduction of high-dose cytarabine did not significantly lower the rate of MRD positivity after Induction I therapy (34% vs. 42%, P=0.17). The cumulative incidences of grade 3 or greater infection were 79.3% ± 4.0% and 75.5% ± 4.2% for patients treated on the high-dose or low-dose arms. The 3-year estimates (± SE) of event-free and overall survival were 63.0% ± 4.1% and 71.1% ± 3.8%, respectively. Achievement of MRD < 0.1% after Induction II identified a large group of patients (80%) with a cumulative incidence of relapse of only 17% ± 3%. Post-Induction I MRD ≥ 1% was the only independent adverse prognostic factor that was statistically significant (P < 0.05) for both event-free (HR, 2.41; CI 1.36–4.26; P=0.003) and overall survival (HR, 2.11; CI 1.09–4.11; P=0.028).
Interpretation
Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve the outcome of childhood AML.
doi:10.1016/S1470-2045(10)70090-5
PMCID: PMC3171799  PMID: 20451454
12.  Ratio of bcl-xshort to bcl-xlong is different in good- and poor-prognosis subsets of acute myeloid leukemia. 
Molecular Medicine  1998;4(3):158-164.
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous collection of leukemic disorders ranging from chemotherapy-sensitive subsets [inversion 16 and t(8;21)], which often can be cured with cytosine arabinoside alone, to the most resistant subsets, which can survive even supralethal levels of combination alkylator chemotherapy (cytogenetic subsets monosomy 5 and monosomy 7). MATERIALS AND METHODS: To analyze the expression of BCL-2 family genes, which are expressed in these subsets of AML, we used PCR sequence amplification reactions that are dependent on oligonucleotide primers representing the BH1 and BH2 homology domains to generate the unique regions between BH1 and BH2. These primers are conserved among all members of the BCL-2 gene family and are separated by a 150 nucleotide region sequence between the BH1 and BH2 domains. The PCR products unique to each BCL-2 family member were cloned directionally into sequencing vectors. The identity of the insert of each clone was determined by slotblots of the DNA amplified from individual colonies and by hybridization with radioactive probes specific to the bcl-2, bcl-x, or bax genes. RESULTS: We found that bcl-2 is the predominant member expressed in AML samples with a poor prognosis (-5, -7), whereas the transcripts of bcl-x are higher than those of bcl-2 in the AML samples with a good prognosis [inv16, t(8;21)]. No significant difference in bax expression was detected between AML subsets of good and bad prognosis. The ratio of bcl-xlong, which inhibits apoptosis, to bcl-xshort, which promotes apoptosis, was determined by amplification with a pair of primers specific to bcl-x followed by separation of the PCR product on agarose gels. Bcl-xlong and bcl-xshort appeared as bands of different molecular mass on a molecular weight gel and were visualized by ethidium bromide staining or Southern blot analysis with a bcl-x-specific probe. CONCLUSIONS: We found that the ratio of bcl-x long to bcl-x short was higher in the AML patients with a poor prognosis. These experiments showed that the levels of BCL-2 family members in the leukemia cells of good- and poor-prognosis subsets are different. In addition, novel members of the BCL-2 family were isolated from the cells of AML patients of either prognosis.
Images
PMCID: PMC2230351  PMID: 9562974
13.  Isoform-Specific Potentiation of Stem and Progenitor Cell Engraftment by AML1/RUNX1  
PLoS Medicine  2007;4(5):e172.
Background
AML1/RUNX1 is the most frequently mutated gene in leukaemia and is central to the normal biology of hematopoietic stem and progenitor cells. However, the role of different AML1 isoforms within these primitive compartments is unclear. Here we investigate whether altering relative expression of AML1 isoforms impacts the balance between cell self-renewal and differentiation in vitro and in vivo.
Methods and Findings
The human AML1a isoform encodes a truncated molecule with DNA-binding but no transactivation capacity. We used a retrovirus-based approach to transduce AML1a into primitive haematopoietic cells isolated from the mouse. We observed that enforced AML1a expression increased the competitive engraftment potential of murine long-term reconstituting stem cells with the proportion of AML1a-expressing cells increasing over time in both primary and secondary recipients. Furthermore, AML1a expression dramatically increased primitive and committed progenitor activity in engrafted animals as assessed by long-term culture, cobblestone formation, and colony assays. In contrast, expression of the full-length isoform AML1b abrogated engraftment potential. In vitro, AML1b promoted differentiation while AML1a promoted proliferation of progenitors capable of short-term lymphomyeloid engraftment. Consistent with these findings, the relative abundance of AML1a was highest in the primitive stem/progenitor compartment of human cord blood, and forced expression of AML1a in these cells enhanced maintenance of primitive potential both in vitro and in vivo.
Conclusions
These data demonstrate that the “a” isoform of AML1 has the capacity to potentiate stem and progenitor cell engraftment, both of which are required for successful clinical transplantation. This activity is consistent with its expression pattern in both normal and leukaemic cells. Manipulating the balance of AML1 isoform expression may offer novel therapeutic strategies, exploitable in the contexts of leukaemia and also in cord blood transplantation in adults, in whom stem and progenitor cell numbers are often limiting.
The truncated "a" isoform of AML1 is shown to have the capacity to potentiate stem and progenitor cell engraftment, both of which are required for successful clinical transplantation.
Editors' Summary
Background.
Blood contains red blood cells (which carry oxygen round the body), platelets (which help the blood to clot), and white blood cells (which fight off infections). All these cells, which are regularly replaced, are derived from hematopoietic stem cells, blood-forming cells present in the bone marrow. Like all stem cells, hematopoietic stem cells self-renew (reproduce themselves) and produce committed progenitor cells, which develop into mature blood cells in a process called hematopoiesis. Many proteins control hematopoiesis, some of which are called transcription factors; these factors bind to DNA through their DNA-binding domain and then control the expression of genes (that is, how DNA is turned into proteins) through particular parts of the protein (their transcription regulatory domains). An important hematopoietic transcription factor is AML1—a protein first identified because of its involvement in acute myelogenous leukemia (AML, a form of blood cancer). Mutations (changes) in the AML1 gene are now known to be present in other types of leukemia, which are often characterized by overproliferation of immature blood cells.
Why Was This Study Done?
Because of AML1′s crucial role in hematopoiesis, knowing more about which genes it regulates and how its activity is regulated could provide clues to treating leukemia and to improving hematopoietic cell transplantation. Many cancer treatments destroy hematopoietic stem cells, leaving patients vulnerable to infection. Transplants of bone marrow or cord blood (the cord that links mother and baby during pregnancy contains peripheral blood stem cells) can replace the missing cells, but cord blood in particular often contains insufficient stem cells for successful transplantation. It would be useful, therefore, to expand the stem cell content of these tissues before transplantation. In this study, the researchers investigated the effect of AML1 on self-renewal and differentiation of hematopoietic stem and progenitor cells in the laboratory (in vitro) and in animals (in vivo). In particular, they have asked how two isoforms (closely related versions) of AML1 affect the ability of these cells to grow and differentiate (engraft) in mice after transplantation.
What Did the Researchers Do and Find?
The researchers artificially expressed AML1a and AML1b (both isoforms contain a DNA binding domain, but only AML1b has transcription regulatory domains) in mouse hematopoietic stem and progenitor cells and then tested the cells' ability to engraft in mice. AML1a-expressing cells engrafted better than unaltered cells and outgrew unaltered cells when transplanted as a mixture. AML1b-expressing cells, however, did not engraft. In vitro, AML1a-expressing cells grew more than AML1b-expressing cells, whereas differentiation was promoted in AML1b-expressing cells. To investigate whether the isoforms have the same effects in human cells, the researchers measured the amount of AML1a and AML1b mRNA (the template for protein production) made by progenitor cells in human cord blood. Although AML1b (together with AML1c, an isoform with similar characteristics) mRNA predominated in all the progenitor cell types, the relative abundance of AML1a was greatest in the stem and progenitor cells. Furthermore, forced expression of AML1a in these cells improved their ability to divide in vitro and to engraft in mice.
What Do These Findings Mean?
These findings indicate that AML1a expression increases the self-renewal capacity of hematopoietic stem and progenitor cells and consequently improves their ability to engraft in mice, whereas AML1b expression encourages the differentiation of these cell types. These activities are consistent with the expression patterns of the two isoforms in normal hematopoietic cells and in leukemic cells—the mutated AML made by many leukemic cells resembles AML1a. Because the AML1 isoforms were expressed at higher than normal levels in these experiments, the physiological relevance of these findings needs to be confirmed by showing that normal levels of AML1a and AML1b produce similar results. Nevertheless, these results suggest that manipulating the balance of AML1 isoforms made by hematopoietic cells might be useful clinically. In leukemia, a shift toward AML1b expression might slow the proliferation of leukemic cells and encourage their differentiation. Conversely, in cord blood transplantation, a shift toward AML1a expression might improve patient outcomes by expanding the stem and progenitor cell populations.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040172.
Wikipedia has pages on hematopoiesis and hematopoietic stem cells (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US National Cancer Institute has a fact sheet on bone marrow and peripheral blood stem cell transplantation (in English and Spanish) and information for patients and professionals on leukemia (in English)
The American Society of Hematology provides patient information about blood diseases, including information on bone marrow and stem cell transplantation
doi:10.1371/journal.pmed.0040172
PMCID: PMC1868041  PMID: 17503961
14.  Plasma Exosomes as Markers of Therapeutic Response in Patients with Acute Myeloid Leukemia 
Purpose: Exosomes isolated from the plasma of newly diagnosed acute myeloid leukemia (AML) patients have elevated protein and transforming growth factor-beta 1 (TGF-β1) contents and inhibit natural killer (NK) cell cytotoxicity (Haematologica 96, p. 1302, 2011). A potential role of exosomes in predicting responses to chemotherapy (CT) was evaluated in AML patients undergoing treatment.
Experimental Design: Plasma was obtained from AML patients at diagnosis (n = 16); post-induction CT (n = 9); during consolidation CT (n = 10); in long-term remission (Lt-CR, n = 5); and from healthy volunteers (n = 7). Exosomes were isolated by size-exclusion chromatography and ultracentrifugation. The exosomal protein, soluble TGFβ-1 levels (ELISA), and the TGF-β1 profiles (western blots) were compared among patients’ cohorts. The results were correlated with the patients’ cytogenetic profile, percentage of leukemic blast, and outcome.
Results: At diagnosis, protein and TGF-β1 levels were higher (p < 0.009 and p < 0.004) in AML than control exosomes. These values decreased after induction CT (p < 0.05 and p < 0.004), increased during consolidation CT (p < 0.02 and p < 0.005), and normalized in Lt-CR. While TGF-β1 and protein levels tracked one another, TGF-β1 pro-peptide, latency-associated peptide (LAP), or mature TGF-β1 differentially decorated exosomes isolated before, during, and after CT. Only TGF-β1 pro-peptide was seen in exosomes of controls or Lt-CR patients. During consolidation CT, exosomes carried TGF-β1 pro-peptide, LAP, and low levels of mature TGF-β1. NK cell co-incubation with AML exosomes carrying all three TGF-β1 forms induced down-regulation of NKG2D expression.
Conclusion: Changes in exosomal protein and/or TGF-β1 content may reflect responses to CT. The exosomal profile may suggest the presence of residual disease in patients considered to have achieved complete remission.
doi:10.3389/fimmu.2014.00160
PMCID: PMC3989594  PMID: 24782865
acute myelogenous leukemia; exosomes; TGF-β1; protein levels; chemotherapy
15.  Timed sequential chemotherapy with concomitant Granulocyte Colony-Stimulating Factor for high-risk acute myelogenous leukemia: a single arm clinical trial 
BMC Cancer  2002;2:12.
Background
The timed-sequential chemotherapy regimen consisting of etoposide, mitoxantrone and cytarabine (EMA) is an effective therapy for relapsed or refractory acute myelogenous leukemia (AML). We postulated that granulocyte colony-stimulating factor (G-CSF) might enhance the cytotoxicity of EMA by increasing the proportion of leukemic blasts in S-phase. We added G-CSF to EMA (EMA-G) for therapy of advanced high-risk AML patients.
Methods
High-risk AML was defined as refractory, relapsed or secondary to either an antecedent hematologic disorder or exposure to cytotoxic agents. The patients were treated with one course of EMA-G consisting of mitoxantrone and cytarabine on days 1–3, and etoposide and cytarabine on days 8–10. G-CSF was started on day 4 and continued until absolute neutrophil count recovered.
Results
Thirty patients were enrolled. The median age was 51 years (range, 25–75). Seventeen (61%) patients had unfavorable cytogenetic karyotypes. Twenty (69%) patients had secondary AML. Ten (34%) had relapsed disease. Four (14%) had refractory AML. Three (10%) patients died from febrile neutropenia and sepsis. Major non-hematologic toxicity included hyperbilirubimenia, renal insufficiency, mucositis, diarrhea, nausea and vomiting, skin rash. A complete remission was achieved in 13 (46%) patients. Median overall survival was 9 months (range, 0.5–66). Median relapse-free survival (RFS) for those who had a CR was 3 months (range, 0.5–63) with RFS censored at the time of allogeneic bone marrow transplantation or peripheral stem cell transplantation for 6 of the patients.
Conclusions
EMA-G is a safe and efficacious option for induction chemotherapy in advanced, high-risk AML patients. The activity of EMA may be increased if applied in patients with less advanced disease.
doi:10.1186/1471-2407-2-12
PMCID: PMC113260  PMID: 12019034
16.  Dose Escalation of Lenalidomide in Relapsed or Refractory Acute Leukemias 
Journal of Clinical Oncology  2010;28(33):4919-4925.
Purpose
Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia.
Patients and Methods
Thirty-one adults with acute myeloid leukemia (AML) and four adults with acute lymphoblastic leukemia (ALL) were enrolled. Lenalidomide was given orally at escalating doses of 25 to 75 mg daily on days 1 through 21 of 28-day cycles to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD), as well as to provide pharmacokinetic and preliminary efficacy data.
Results
Patients had a median age of 63 years (range, 22 to 79 years) and a median of two prior therapies (range, one to four therapies). The DLT was fatigue; 50 mg/d was the MTD. Infectious complications were frequent. Plasma lenalidomide concentration increased proportionally with dose. In AML, five (16%) of 31 patients achieved complete remission (CR); three of three patients with cytogenetic abnormalities achieved cytogenetic CR (none with deletion 5q). Response duration ranged from 5.6 to 14 months. All responses occurred in AML with low presenting WBC count. No patient with ALL responded. Two of four patients who received lenalidomide as initial therapy for AML relapse after allogeneic transplantation achieved durable CR after development of cutaneous graft-versus-host disease, without donor leukocyte infusion.
Conclusion
Lenalidomide was safely escalated to 50 mg daily for 21 days, every 4 weeks, and was active with relatively low toxicity in patients with relapsed/refractory AML. Remissions achieved after transplantation suggest a possible immunomodulatory effect of lenalidomide, and results provide enthusiasm for further studies in AML, either alone or in combination with conventional agents or other immunotherapies.
doi:10.1200/JCO.2010.30.3339
PMCID: PMC3020696  PMID: 20956622
17.  POU4F1 is associated with t(8;21) acute myeloid leukemia and contributes directly to its unique transcriptional signature 
The t(8;21)(q22;q22) translocation, present in ~5% of adult acute myeloid leukemia (AML) cases, produces the AML1/ETO fusion protein. Dysregulation of the POU domain-containing transcription factor POU4F1 is a recurring abnormality in t(8;21) AML. Here, we show that POU4F1 over-expression is highly correlated with, but not caused by AML1/ETO. AML1/ETO markedly increases the self-renewal capacity of myeloid progenitors from murine bone marrow or fetal liver and drives expansion of these cells in liquid culture. POU4F1 is neither necessary nor sufficient for these AML1/ETO-dependent properties, suggesting that it contributes to leukemia through novel mechanisms. To identify targets of POU4F1, we performed gene expression profiling in primary mouse cells with genetically defined levels of POU4F1 and identified 140 differentially expressed genes. This expression signature was significantly enriched in human t(8;21) AML samples and was sufficient to cluster t(8;21) AML samples in an unsupervised hierarchical analysis. Among the most highly differentially expressed genes, half are known AML1/ETO targets, implying that the unique transcriptional signature of t(8;21) AML is, in part, attributable to POU4F1 and not AML1/ETO itself. These genes provide novel candidates for understanding the biology and developing therapeutic approaches for t(8;21) AML.
doi:10.1038/leu.2010.61
PMCID: PMC2868953  PMID: 20376082
POU4F1; AML1/ETO; acute myeloid leukemia; gene expression profiling
18.  HLA-Identical Sibling Allogeneic Transplants versus Chemotherapy in Acute Myelogenous Leukemia with t(8;21) in First Complete Remission: Collaborative Study Between the German AML Intergroup and CIBMTR 
We studied the role of HLA-matched sibling hematopoietic cell transplantation (HCT) in treating t(8;21) AML in first remission. Outcomes of 118 patients receiving HCT and reported to the Center for International Blood and Marrow Transplant Research were compared with 132 similar patients receiving chemotherapy selected from eight German AML Intergroup multicenter trials. Characteristics of the cohorts were similar except that chemotherapy recipients were significantly older. To adjust for time to treatment bias, outcomes were compared using left-truncated Cox regression models. Transplants were associated with higher treatment-related mortality [relative risk (RR) 6.76, 95% confidence interval (CI) 2.95–15.45, p<0.001], lower relapse (RR 0.47, 95% CI 0.25–0.85, p=0.01) and similar relapse-free survival (p=0.2). Loss of sex chromosomes (LOS) in addition to t(8;21) negatively impacted overall survival in patients receiving chemotherapy. Patients without LOS experienced shorter survival after HCT comparing to chemotherapy (RR 3.05, p=0.02), whereas patients with LOS had similar survival regardless of postremission therapy. In both cohorts, white blood cell count (WBC) at diagnosis > 25 x109/L was associated with a higher relapse risk (RR=2.09, p=0.03), lower relapse-free (RR=1.9, p=0.008) and overall survival (RR=1.91, p=0.01). In this cohort of patients with t(8;21) AML , HCT did not improve overall survival, since reduction of relapse was offset by high transplant-related mortality. In the group without LOS, survival after chemotherapy was far superior to HCT. These results suggest that patients with t(8;21) AML without poor prognostic factors have higher rates of survival after chemotherapy as a post remission therapy compared to HCT.
doi:10.1016/j.bbmt.2007.10.006
PMCID: PMC2531160  PMID: 18215779
t(8;21); AML; hematopoietic stem cell transplantation; chemotherapy
19.  The G516T CYP2B6 Germline Polymorphism Affects the Risk of Acute Myeloid Leukemia and Is Associated with Specific Chromosomal Abnormalities 
PLoS ONE  2014;9(2):e88879.
The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G516T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G516T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations.
doi:10.1371/journal.pone.0088879
PMCID: PMC3933334  PMID: 24586425
20.  Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/Refractory Leukemia 
Journal of Clinical Oncology  2011;29(24):3293-3300.
Purpose
To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.
Patients and Methods
Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m2) and clofarabine (stratum one: 40 mg/m2, n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m2, n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m2 and 150 mg/m2 twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.
Results
At sorafenib 200 mg/m2, two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m2. Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3–internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.
Conclusion
Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
doi:10.1200/JCO.2011.34.7427
PMCID: PMC3158600  PMID: 21768474
21.  MECHANISMS OF SYNERGISTIC ANTILEUKEMIC INTERACTIONS BETWEEN VALPROIC ACID AND CYTARABINE IN PEDIATRIC ACUTE MYELOID LEUKEMIA 
Purpose
To determine the possibility of synergistic anti-leukemic activity and the underlying molecular mechanisms associated with cytarabine combined with valproic acid (VPA) [a histone deacetylase inhibitor (HDACI) and an FDA-licensed drug for treating both children and adults with epilepsy] in pediatric acute myeloid leukemia (AML).
Experimental Design
The type and extent of anti-leukemic interactions between cytarabine and VPA in clinically relevant pediatric AML cell lines and diagnostic blasts from children with AML were determined by MTT assays and standard isobologram analyses. The effects of cytarabine and VPA on apoptosis and cell cycle distributions were determined by flow cytometry analysis and caspase enzymatic assays. The effects of the two agents on DNA damage and Bcl-2 family proteins were determined by Western blotting.
Results
We demonstrated synergistic antileukemic activities between cytarabine and VPA in 4 pediatric AML cell lines and 9 diagnostic AML blast samples. t(8;21) AML blasts were significantly more sensitive to VPA and showed far greater sensitivities to combined cytarabine and VPA than non-t(8;21) AML cases. Cytarabine and VPA cooperatively induced DNA double strand breaks, reflected in induction of γH2AX and apoptosis, accompanied by activation of caspases 9 and 3. Further, VPA induced Bim expression and shRNA knockdown of Bim resulted in significantly decreased apoptosis induced by cytarabine, and by cytarabine plus VPA.
Conclusions
Our results establish global synergistic antileukemic activity of combined VPA and cytarabine in pediatric AML and provide compelling evidence to support the use of VPA in the treatment of children with this deadly disease.
doi:10.1158/1078-0432.CCR-10-1707
PMCID: PMC3018695  PMID: 20889917
22.  Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005–2011 – experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) 
Contemporary Oncology  2014;18(1):48-53.
Aim of the study
Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011.
Material and methods
The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children.
Results
Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1.
Conclusions
The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy.
doi:10.5114/wo.2014.40436
PMCID: PMC4037997  PMID: 24876821
acute myeloid leukemia; relapse; stem cell transplantation; children
23.  Acute Myeloid Leukemia Presenting as Acute Appendicitis 
Case Reports in Hematology  2013;2013:815365.
Appendicitis in leukemic patients is uncommon but associated with increased mortality. Additionally, leukemic cell infiltration of the appendix is extremely rare. While appendectomy is the treatment of choice for these patients, diagnosis and management of leukemia have a greater impact on remission and survival. A 59-year-old Caucasian female was admitted to the surgical service with acute right lower quadrant pain, nausea, and anorexia. She was noted to have leukocytosis, anemia, and thrombocytopenia. Abdominal imaging demonstrated appendicitis with retroperitoneal and mesenteric lymphadenopathy for which she underwent laparoscopic appendectomy. Peripheral smear, bone marrow biopsy, and surgical pathology of the appendix demonstrated acute myeloid leukemia (AML) with nonsuppurative appendicitis. In the setting of AML, prior cases described the development of appendicitis with active chemotherapy. Of these cases, less than ten patients had leukemic infiltration of the appendix, leading to leukostasis and nonsuppurative appendicitis. Acute appendicitis with leukemic infiltration as the initial manifestation of AML has only been described in two other cases in the literature with an average associated morbidity of 32.6 days. The prompt management in this case of appendicitis and AML resulted in an overall survival of 185 days.
doi:10.1155/2013/815365
PMCID: PMC3693109  PMID: 23840984
24.  IDENTIFICATION AND CHARACTERIZATION OF NOVEL AML1-ETO FUSION TRANSCRIPTS IN PEDIATRIC t(8;21) ACUTE MYELOID LEUKEMIA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP 
Oncogene  2008;27(36):4933-4942.
t(8;21)(q22;q22) results in the AML1-ETO (A1E) fusion gene and is a common cytogenetic abnormality in acute myeloid leukemia (AML). Although insertions at the breakpoint region of the A1E fusion transcripts have been reported, additional structural alterations are largely uncharacterized. By RT-PCR amplifications and DNA sequencing, numerous in-frame and out-of-frame AML1b-ETO and AML1c-ETO transcripts were identified in 13 pediatric t(8;21) AMLs, likely resulting from alternate splicing, internal deletions, and/or breakpoint region insertions involving both the AML1 (RUNX1) and ETO regions. The in-frame A1E fusion transcript forms represented minor forms. These structure alterations were found in AML1c-ETO but not AML1b-ETO transcripts in 2 adult t(8;21) AMLs. Although no analogous alterations were detected in native AML1b transcripts, identical alterations in native ETO transcripts were identified. When transfected into HeLa cells, only AML1b, and not the in-frame A1E forms, transactivated the GM-CSF promoter. In co-transfection experiments, the effects of A1E proteins on GM-CSF transactivation by AML1b ranged from repressive to activating. Our results demonstrate a remarkable and unprecedented heterogeneity in A1E fusion transcripts in t(8;21) myeloblasts and suggest that synthesis of alternate A1E transcript and protein forms can significantly impact the regulation of AML1 responsive genes.
doi:10.1038/onc.2008.134
PMCID: PMC3763903  PMID: 18469864
t(8;21); AML1-ETO; acute myeloid leukemia; fusion transcripts
25.  Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics 
Acute myeloid leukemia (AML) is a heterogenous disorder that results from a block in the differentiation of hematopoietic progenitor cells along with uncontrolled proliferation. In approximately 60% of cases, specific recurrent chromosomal aberrations can be identified by modern cytogenetic techniques. This cytogenetic information is the single most important tool to classify patients at their initial diagnosis into three prognostic categories: favorable, intermediate, and poor risk. Currently, favorable risk AML patients are usually treated with contemporary chemotherapy while poor risk AML patients receive allogeneic stem cell transplantation if suitable stem cell donors exist. The largest subgroup of AML patients (~40%) have no identifiable cytogenetic abnormalities and are classified as intermediate risk. The optimal therapeutic strategies for these patients are still largely unclear. Recently, it is becoming increasingly evident that it is possible to identify a subgroup of poorer risk patients among those with normal cytogenic AML (NC-AML). Molecular risk stratification for NC-AML patients may be possible due to mutations of NPM1, FLT3, MLL, and CEBPα as well as alterations in expression levels of BAALC, MN1, ERG, and AF1q. Further prospective studies are needed to confirm if poorer risk NC-AML patients have improved clinical outcomes after more aggressive therapy.
doi:10.1186/1756-8722-2-23
PMCID: PMC2700131  PMID: 19490647

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