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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.
PMCID: PMC1770248  PMID: 14990611
mastocytosis; bone marrow; CD25; acute myeloid leukaemia; mast cell tryptase; occult; mastocytosis; c-kit mutation
2.  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.
PMCID: PMC3589638  PMID: 23483057
Systemic mastocytosis; Acute myeloid leukemia; Aleukemic mast cell leukemia; Allogeneic hematopoietic stem cell transplantation
3.  Acute myeloid leukemia with t(10;17)(p13;q12) chromosome translocation: a case report and literature review 
More than 50% of adult patients with acute myeloid leukemia (AML) carry chromosome abnormalities, like t(8;21)(q22;q22), t(15;17), t(8;21)inv(16) or t(16;16). t(10;17) translocation was very rare in AML. There are only 10 such cases reported in the literature. Here, we describe a case of acute myeloid leukemia with t(10;17)(p13;q12) chromosome translocation, who had complete remission after one course of chemotherapy.
PMCID: PMC3512178  PMID: 23226626
Acute myeloid leukemia; t(10;17)(p13;q12); chromosome translocation
4.  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.
PMCID: PMC133929  PMID: 12101243
5.  Systemic mastocytosis with associated acute myelogenous leukemia 
Systemic mastocytosis (SM) is a condition associated with a clonal neoplastic proliferation of mast cells. Approximately 40% of patients with SM present with an associated clonal hematological non–mast cell lineage disorder. Patients presenting with SM–acute myeloid leukemia (AML) have the worst prognosis. We present a case of a 62-year-old woman who was diagnosed with SM-AML. After initial treatment with a standard regimen of cytosine arabinoside (Ara-C)/idarubicin, her bone marrow showed residual blasts. She was subsequently treated with a second induction regimen of clofarabine and high-dose Ara-C, which resulted in remission of AML, although a residual mast cell infiltrate persisted in her bone marrow. After consolidation therapy with clofarabine/Ara-C, the patient received a stem cell allograft. A follow-up bone marrow showed no residual blasts but persistent mast cells occupying about 5% of the marrow volume.
PMCID: PMC3862125  PMID: 24381396
6.  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.
PMCID: PMC3787645  PMID: 24109526
7.  Patients with Fanconi Anemia and AML have Different Cytogenetic Clones than de novo Cases of AML 
Pediatric blood & cancer  2012;59(5):922-924.
Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9) and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management.
PMCID: PMC3407278  PMID: 22517793
Acute myelogenous leukemia; Fanconi anemia; cytogenetics; clones; sporadic AML
8.  Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation 
Cancer Biology & Medicine  2013;10(4):232-235.
Myeloid sarcoma (MS) is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia (AML). This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis of AML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission (CR) was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography (PET-CT). Radiotherapy was performed for the localized mass after a multidisciplinary team (MDT) discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia.
PMCID: PMC3860347  PMID: 24349834
Myeloid sarcoma (MS); acute myeloid leukemia (AML); allogeneic hematopoietic stem cell transplantation; multidisciplinary team (MDT)
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.
PMCID: PMC3100545  PMID: 21629739
10.  A Case Report of the Second de Novo Acute Myeloid Leukemia (AML) Following Allogeneic Stem Cell Transplantation in a Patient with the First AML 
Secondary leukemia occurring after hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) is rare. Secondary AML usually follows autologous and not allogeneic transplants. When a new leukemia develops in a patient successfully treated with an allogeneic HSCT, the possibility of a de novo or secondary leukemia from either the donor or recipient should be considered. We present a case initially diagnosed as de novo AML without a cytogenetic abnormality. The patient was successfully treated with an HLA-matched sibling allogeneic HSCT. However, more than six years later, AML developed again and was associated with new complex cytogenetic abnormalities. After a second HSCT, the patient has been followed without serious complications. Considering the allogeneic setting, the newly developed cytogenetic abnormalities, a relatively long latent period, and the good clinical course after the second allogeneic HSCT, this case might represent a second de novo AML following successful treatment of the first AML.
PMCID: PMC2829408  PMID: 20195413
Leukemia, myeloid, acute; Hematopoietic stem cell transplantation
11.  Trisomy 11 as an isolated abnormality in acute myeloid leukemia is associated with unfavorable prognosis but not with an NPM1 or KIT mutation 
Trisomy 11 (+11) as an isolated abnormality is a rare event in patients with acute myeloid leukemia (AML) and is associated with poor prognosis. We describe the clinicopathologic features of 18 AML patients with isolated +11 and their mutation status of NPM1, FLT3, NRAS ,KRAS, and KIT. Fourteen patients had de novo AML and 4 patients had a history of myelodysplastic syndrome (MDS). Fifteen patients had a progressive clinical course with refractory or relapsed disease. The median overall survival was 5 months (range, 2 to 48 months). Only 1 patient achieved complete remission after undergoing stem cell transplantation. The bone marrow median blast count was 65% (range, 22 to 86) and 14 patients had blasts >50%. The most common type of AML was AML without maturation (7 patients) classified by the World Health Organization classification system, or M1 (10 patients) by the French-American-British (FAB) system. FLT3 mutations were detected in 3 of 15 (20%) cases tested. RAS mutation was present in 1 of 16 (6%) cases and there was no evidence of NPM1 of KIT mutations (each tested in 12 cases). Our findings confirm previous reports that isolated +11 is associated with a poor prognosis in patients with AML and tends to be associated with FAB-M1 morphologic features. No evidence of NPM1 or KIT mutations were identified.
PMCID: PMC3093062  PMID: 21577323
Isolated trisomy 11; acute myeloid leukemia; gene mutations; prognosis
12.  Recent advances in the treatment of acute myeloid leukemia 
Acute myeloid leukemia (AML) is a disorder with significant molecular and clinical heterogeneity. Although there have been clear advances in the identification of somatic genetic and epigenetic alterations present in the malignant cells of patients with AML, translating this knowledge into an integrated view with an impact on the clinical treatment of AML has been slower to evolve. Recent clinical advances in the treatment of AML include studies demonstrating the benefit of dose-intense daunorubicin therapy in induction chemotherapy for patients of any age. We also review use of the DNA methyltransferase inhibitor azacitidine for treatment of AML in elderly patients as well as a study of global patterns of DNA methylation in patients with AML. Lastly, we review a recent assessment of the role of allogeneic hematopoietic stem cell transplantation in AML in first complete remission.
PMCID: PMC2927833  PMID: 20798782
13.  Recent advances in the treatment of acute myeloid leukemia 
Acute myeloid leukemia (AML) is a disorder with significant molecular and clinical heterogeneity. Although there have been clear advances in the identification of somatic genetic and epigenetic alterations present in the malignant cells of patients with AML, translating this knowledge into an integrated view with an impact on the clinical treatment of AML has been slower to evolve. Recent clinical advances in the treatment of AML include studies demonstrating the benefit of dose-intense daunorubicin therapy in induction chemotherapy for patients of any age. We also review use of the DNA methyltransferase inhibitor azacitidine for treatment of AML in elderly patients as well as a study of global patterns of DNA methylation in patients with AML. Lastly, we review a recent assessment of the role of allogeneic hematopoietic stem cell transplantation in AML in first complete remission.
PMCID: PMC2927833  PMID: 20798782
14.  A case of acute myeloid leukemia-M2 with trisomy 4 in addition to t(8;21) 
t(8;21)(q22;q22) is the most frequently observed karyotypic abnormality associated with acute myeloid leukemia (AML), specifically in FAB-M2. Short-term unstimulated bone marrow (BM) and peripheral blood lymphocyte culture showed 47,XX, +4,t(8;21) in all metaphase plates; and interphase and metaphase results of AML-ETO fusion was positive and trisomy of 4 was confirmed with WCP probes. Trisomy 4 in AML with t(8;21) is a rare numerical abnormality. Here we present such case of patient which may constitute a distinctive subtype.
PMCID: PMC2840780  PMID: 20300287
Acute myeloid leukemia; cytogenetics; fluorescence in situ hybridization
15.  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.
PMCID: PMC2700131  PMID: 19490647
16.  Treatment of acute erythroleukemia with Azacitidine: A case series 
Leukemia Research Reports  2013;2(2):41-43.
Acute erythroleukemia (AEL) is a rare form of acute myeloid leukemia (AML) often associated with a poor prognosis. It is more frequent in elderly patients, limiting the use aggressive therapies. Azacitidine is a hypomethylating agent with recognized efficacy in high risk myelodysplasia and AML in the elderly. Here we report 5 cases of AEL treated with Azacitidine. The cohort included 4 men and 1 woman, median age 70. One patient had been refractory to intensive chemotherapy, the others received Azacitidine as first line. Treatment was well tolerated. Four patients achieved transfusion independence. Two patients achieved complete remission and 1 achieved partial remission. After a median follow up time of 20 months, the median survival of the cohort was 20 months. Three patients died of disease progression. These results confirm the therapeutic value of Azacitidine in AEL.
PMCID: PMC3850371  PMID: 24371777
Erythroleukemia; Azacytidine; Hypomethylating agents
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.
PMCID: PMC3763903  PMID: 18469864
t(8;21); AML1-ETO; acute myeloid leukemia; fusion transcripts
18.  Therapy related acute myeloid leukemia with t(10:16): a rare entity 
Hematology Reports  2011;3(3):e23.
Treatment related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are well known complications after chemotherapy for various hematologic and non-hematologic malignancies. Alkylating agents and Topoisomerase inhibitors are most widely studied in this regard. There is growing concern about occurrence of t-MDS, t-MDS/AML and t-AML in patients of CLL treated with nucleoside analogues especially in combination with alkylating agents. Exact incidence and pathogenesis of nucleoside analogue related MDS/AML is not clear at this time. We hereby report a case of t-AML in a patient treated with Fludarabine, Cyclophosphamide and Rituximab (FCR) for CLL. The cytogenetic studies revealed a unique translocation t (10:16), that has been reported in very few cases of therapy related AML and pediatric AML.
PMCID: PMC3269801  PMID: 22593815
acute myeloid leukemia; myelodysplastic syndrome.
19.  A complete remission can be achieved despite persistence of abnormal bone marrow promyelocytes in acute promyelocytic leukemia--experience in 2 patients. 
Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) and is distinguished from other subsets of AML by its distinctive morphology, specific chromosomal abnormality, associated consumptive coagulopathy, and response to treatment. Interestingly, patients with APL frequently enter complete remission without undergoing a characteristic period of bone marrow hypoplasia. In two cases in this report, complete remission was achieved without bone marrow hypoplasia without further additional course of chemotherapy despite the appearance of persistent malignant cells in the bone marrow after first induction chemotherapy. During the period of treatment, severe coagulopathy occurred in both cases but resolved as the patients entered into remission. Remission in patients with APL may occur even when induction therapy fails to cause marrow hypoplasia or to eradicate replicative cells. To avoid unnecessary exposure to toxic therapy, caution should be exercised in assessing the adequacy of remission induction treatment.
PMCID: PMC3053749  PMID: 8198760
20.  Impact of Pretransplantation Minimal Residual Disease, As Detected by Multiparametric Flow Cytometry, on Outcome of Myeloablative Hematopoietic Cell Transplantation for Acute Myeloid Leukemia 
Journal of Clinical Oncology  2011;29(9):1190-1197.
Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD).
Patients and Methods
We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive.
Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD-positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD-negative HCT.
These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.
PMCID: PMC3083874  PMID: 21282535
21.  Detection of FLT3 Oncogene Mutations in Acute Myeloid Leukemia Using Conformation Sensitive Gel Electrophoresis 
FLT3 (fms-related tyrosine kinase 3) is a receptor tyrosine kinase class III that is expressed on by early hematopoietic progenitor cells and plays an important role in hematopoietic stem cell proliferation, differentiation and survival. FLT3 is also expressed on leukemia blasts in most cases of acute myeloid leukemia (AML). In order to determine the frequency of FLT3 oncogene mutations, we analyzed genomic DNA of adult de novo acute myeloid leukemia (AML). Polymerase chain reaction (PCR) and conformation-sensitive gel electrophoresis (CSGE) were used for FLT3 exons 11, 14, and 15, followed by direct DNA sequencing. Two different types of functionally important FLT 3 mutations have been identified. Those mutations were unique to patients with inv(16), t(15:17) or t(8;21) and comprised fifteen cases with internal tandem duplication (ITD) mutation in the juxtamembrane domain and eleven cases with point mutation (exon 20, Asp835Tyr). The high frequency of the flt3 proto-oncogene mutations in acute myeloid leukemia AML suggests a key role for the receptor function. The association of FLT3 mutations with chromosomal abnormalities invites speculation as to the link between these two changes in the pathogenesis of acute myeloid leukemiaAML. Furthermore, CSGE method has shown to be a rapid and sensitive screening method for detection of nucleotide alteration in FLT3 gene. Finally, this study reports, for the first time in Saudi Arabia, mutations in the human FLT3 gene in acute myeloid leukemia AML patients.
PMCID: PMC2635624  PMID: 19330068
AML; Flt3; ITD; CSGE; Mutational analysis
22.  Altered Runx1 Subnuclear Targeting Enhances Myeloid Cell Proliferation and Blocks Differentiation by activating a miR-24/MKP-7/MAP Kinase Network 
Cancer research  2009;69(21):8249-8255.
Disruption of Runx1/AML1 subnuclear localization, either by a single amino acid substitution or by a chromosomal translocation (e.g. t(8;21)), is linked to the etiology of acute myeloid leukemia (AML). Here we show that this defect induces a select set of micro-RNAs (miRs) in myeloid progenitor cells and AML patients with t(8;21). Both Runx1 and the t(8;21)-encoded AML1-ETO occupy the miR-24-23-27 locus and reciprocally control miR-24 transcription. miR-24 directly downregulates MAPK Phosphatase-7 and enhances phosphorylation of both JNK and p38 kinases. Expression of miR-24 stimulates myeloid cell growth, renders proliferation independent of IL3 and blocks granulocytic differentiation. Thus, compromised Runx1 function induces a miR-dependent mechanism that, through MAPK signaling, enhances myeloid proliferation but blocks differentiation, key steps that contribute to leukemia.
PMCID: PMC2995702  PMID: 19826043
cancer; leukemia; AML1-ETO; chromosomal translocation; micro RNA; AML
23.  Granulocytic sarcoma of the small bowel, greater omentum and peritoneum associated with a CBFβ/MYH11 fusion and inv(16) (p13q22): a case report 
Granulocytic sarcoma (GS) is an extramedullary disease which is composed of immature myeloid cells or myeloblasts and usually occurs in association with acute myeloid leukemia (AML), as an initial presentation or a relapse. GS has been associated with various cytogenetic abnormalities, particularly with the t(8;21) translocation and less frequently the inv(16) type.
Case presentation
We present a rare case of GS of the small bowel, greater omentum and peritoneum, which caused obstruction, in a patient with AML associated with a CBFβ/MYH11 fusion gene and an inv(16) (p13q22). In this patient there was only mild myeloid hyperplasia in bone marrow aspiration but molecular analysis identified a CBFβ-MYH11 fusion and inv(16) (p13;q22).
Because of its nonspecific clinical and radiologic findings, this entity can be misdiagnosed and can mimic other solid neoplasms, making it a diagnostic challenge. In a GS with no or minimal morphological changes in bone marrow aspiration it is very important to perform a cytogenetic analysis to benefit from the diagnosis and therapeutic strategy.
PMCID: PMC3032668  PMID: 21255400
24.  Low Risk of Chronic Graft Versus Host Disease and Relapse Associated with T-Cell Depleted Peripheral Blood Stem Cell Transplantation for Acute Myeloid Leukemia in First Remission: Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303 
Graft versus host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) in complete remission (CR) remains unclear. We therefore performed a Phase 2 single arm multi-center study to evaluate the role of TCD in AML patients in CR1 or CR2 up to the age of 65 years. The primary objective was to achieve a disease-free survival (DFS) rate at 6 months post transplant that exceeded 75%. 44 patients with AML in CR1 (N=37) or CR2 (N=7) with a median age of 48.5 years (range 21–59) received myeloablative chemotherapy and fractionated total body irradiation (TBI, 1,375cGy) followed by immunomagnetically selected CD34-enriched, T-cell depleted allografts from HLA-identical siblings. No pharmacological GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grades 2–4 was 22.7%. The incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 at 36 months was 17.4%. With a median follow up of 34 months, disease free survival (DFS) for all patients at 6 months was 82%. DFS for pts in CR1 was 72.8% and 58% at 12 and 36 months, respectively. HCT following myeloablative chemoradiotherapy can be performed in a multi-center setting using a uniform method of TCD resulting in a low risk of extensive chronic GVHD and relapse for pts with AML in CR1.
PMCID: PMC3150599  PMID: 21320619
25.  Advances in molecular genetics and treatment of core-binding factor acute myeloid leukemia 
Current opinion in oncology  2008;20(6):711-718.
Purpose of review Core-binding factor (CBF) acute myeloid leukemia (AML) is among the most common cytogenetic subtypes of AML, being detected in approximately 13% of adults with primary disease. Although CBF-AML is associated with a relatively favorable prognosis, only one-half of the patients are cured. Herein we review recent discoveries of genetic and epigenetic alterations in CBF-AML that may represent novel prognostic markers and therapeutic targets and lead to improvement of the still disappointing clinical outcome of these patients.
Recent findings Several acquired gene mutations and gene-expression and microRNA-expression changes that occur in addition to t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22), the cytogenetic hallmarks of CBF-AML, have been recently reported. Alterations that may represent cooperative events in CBF-AML leukemogenesis include mutations in the KIT, FLT3, JAK2 and RAS genes, haploinsufficiency of the putative tumor suppressor genes TLE1 and TLE4 in t(8;21)-positive patients with del(9q), MN1 overexpression in inv(16) patients, and epigenetic and posttranscriptional silencing of CEBPA. Genome-wide gene-expression and microRNA-expression profiling identifying subgroups of CBF-AML patients with distinct molecular signatures, different clinical outcomes, or both, have also been reported.
Summary Progress has been made in delineating the genetic basis of CBF-AML that will likely result in improved prognostication and development of novel, risk-adapted therapeutic approaches.
PMCID: PMC3677535  PMID: 18841055
acute myeloid leukemia; core-binding factor; gene-expression profiling; JAK2; KIT; MN1

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