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1.  Umbilical Cord Blood Transplantation-associated Nephrotic Syndrome Successfully Treated by Low-density Lipoprotein Apheresis 
Internal Medicine  2016;55(19):2831-2836.
The development of nephrotic syndrome (NS) after umbilical cord transplantation (UBT) has been reported in only four cases to date. We herein report the case of a 50-year-old woman who developed NS 94 days after UBT. She fell into oliguria and required dialysis. A kidney biopsy revealed focal and segmental glomerulosclerosis. Although glucocorticoid monotherapy did not improve her condition, the addition of low-density lipoprotein (LDL) apheresis resulted in remission of NS, a drastic improvement in her renal function, and withdrawal from dialysis. To the best of our knowledge, this is the first report of UBT-associated NS treated with LDL apheresis.
PMCID: PMC5088545  PMID: 27725544
umbilical cord blood transplantation; nephrotic syndrome; LDL apheresis; focal segmental glomerulosclerosis
2.  Identification of Nedd9 as a TGF-β-Smad2/3 Target Gene Involved in RANKL-Induced Osteoclastogenesis by Comprehensive Analysis 
PLoS ONE  2016;11(6):e0157992.
TGF-ß is a multifunctional cytokine that is involved in cell proliferation, differentiation and function. We previously reported an essential role of the TGF-ß -Smad2/3 pathways in RANKL-induced osteoclastogenesis. Using chromatin immunoprecipitation followed by sequencing, we comprehensively identified Smad2/3 target genes in bone marrow macrophages. These genes were enriched in the gene population upregulated by TGF-ß and downregulated by RANKL. Recent studies have revealed that histone modifications, such as trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3), critically regulate key developmental steps. We identified Nedd9 as a Smad2/3 target gene whose histone modification pattern was converted from H3K4me3(+)/H3K4me27(+) to H3K4me3(+)/H3K4me27(-) by TGF-ß. Nedd9 expression was increased by TGF-ß and suppressed by RANKL. Overexpression of Nedd9 partially rescued an inhibitory effect of a TGF-ß inhibitor, while gene silencing of Nedd9 suppressed RANKL-induced osteoclastogenesis. RANKL-induced osteoclastogenesis were reduced and stimulatory effects of TGF-ß on RANKL-induced osteoclastogenesis were partially abrogated in cells from Nedd9-deficient mice although knockout mice did not show abnormal skeletal phenotypes. These results suggest that Nedd9 is a Smad2/3 target gene implicated in RANKL-induced osteoclastogenesis.
PMCID: PMC4918979  PMID: 27336669
4.  DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation 
Nature Communications  2016;7:10924.
Despite the clinical impact of DNMT3A mutation on acute myeloid leukaemia, the molecular mechanisms regarding how this mutation causes leukaemogenesis in vivo are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant haematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are downregulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells, representing a DNA methylation-independent role of mutated DNMT3A. DNMT3A R882H also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, the DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), causing transcriptional silencing, revealing a DNA methylation-independent role of DNMT3A mutation. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. From our data, it is shown that DNMT3A mutants can block the differentiation of HSCs and leukaemic cells via PRC1. This interaction could be targetable in DNMT3A-mutated leukaemias.
DNMT3A mutations are known to cause acute myeloid leukaemia. Here, Koya et al. show that DNMT3A R882H mutation causes monoblastic transformation and haematopoietic stem cell accumulation in a methylation-independent manner, by suppressing the polycomb repressive complex 1, causing transcriptional silencing.
PMCID: PMC4820786  PMID: 27010239
5.  miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target 
Scientific Reports  2016;6:19204.
The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor prognostic leukemia.
PMCID: PMC4709720  PMID: 26754824
6.  Cerebral embolism through hematogenous dissemination of pulmonary mucormycosis complicating relapsed leukemia 
Invasive mucormycosis in patients with hematological diseases mostly occurs in the lungs. Invasive mucormycosis of other anatomical sites is relatively infrequent and its pathogenesis has not so far been well elucidated. Here, we describe an autopsy case of pulmonary invasive mucormycosis complicated by cerebral embolism with infarct. A 77-year-old Japanese woman with relapsed acute myeloid leukemia complained of left visual disturbance and weakness of the lower limbs. The diagnosis of leukemic infiltration to the central nervous system was made. Repeated intrathecal injection of methotrexate plus cytarabine resulted in partial amelioration of the neurologic symptoms. However, the patient then developed fever, dyspnea, and subsequent right hemiparesis. A computed tomography (CT) scan showed a consolidative shadow with halo sign in the left lung field, which was compatible with either invasive pulmonary aspergillosis or mucormycosis. These findings accounted for fever and dyspnea, but not hemiparesis. Despite antifungal therapy, the patient succumbed to death after two weeks. Autopsy revealed pulmonary invasive mucormycosis with a fungal ball in the lumina of the adjacent ascending aorta. Intriguingly, autopsy and postmortem CT scan identified left cerebral infarct due to mucormycosis, which accounted for the right hemiparesis. It is likely that the fungal ball caused the cerebral embolism through hematogenous dissemination. We should suspect hematogenous dissemination when we see a patient with pulmonary invasive mucormycosis developing neurologic symptoms.
PMCID: PMC4680534  PMID: 26722589
Cerebral embolism; hematogenous dissemination; invasive mucormycosis; relapsed acute myeloid leukemia
7.  Clinical significance of high-dose cytarabine added to cyclophosphamide/total-body irradiation in bone marrow or peripheral blood stem cell transplantation for myeloid malignancy 
Addition of high-dose cytarabine (HDCA) to the conventional cyclophosphamide/total-body irradiation (CY/TBI) regimen significantly improved prognosis after cord blood transplantation (CBT) for adult acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The efficacy of HDCA in bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), however, has not yet been elucidated.
We conducted a cohort study to compare the prognosis of HDCA/CY/TBI (N = 435) and CY/TBI (N = 1667) in BMT/PBSCT for AML/MDS using a Japanese transplant registry database. The median age was 38 years, and 86.0 % of the patients had AML. Unrelated donors comprised 54.6 %, and 63.9 % of donors were human leukocyte antigen (HLA)-matched. Overall survival (OS) was not improved in the HDCA/CY/TBI group (adjusted hazard ratio (HR), 1.14; p = 0.13). Neutrophil engraftment was inferior (HR, 0.80; p < 0.01), and the incidence of hemorrhagic cystitis and thrombotic microangiopathy increased in HDCA/CY/TBI (HR, 1.47 and 1.60; p = 0.06 and 0.04, respectively), leading to significantly higher non-relapse mortality (NRM; HR, 1.48; p < 0.01). Post-transplant relapse and tumor-related mortality were not suppressed by the addition of HDCA.
This study indicated the inefficacy of HDCA/CY/TBI in BMT/PBSCT for AML/MDS. Our results should be validated in large-scale prospective studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0201-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4559384  PMID: 26337829
8.  Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice 
Cell metabolism  2014;19(4):593-604.
Prdm16 is a transcription factor that regulates the thermogenic gene program in brown and beige adipocytes. However, whether Prdm16 is required for the development or physiological function of brown adipose tissue (BAT) in vivo has been unclear. By analyzing mice that selectively lacked Prdm16 in the brown adipose lineage, we found that Prdm16 was dispensable for embryonic BAT development. However, Prdm16 was required in young mice to suppress the expression of white fat-selective genes in BAT through recruitment of the histone methyltransferase Ehmt1. Additionally, Prdm16-deficiency caused a severe adult-onset decline in the thermogenic character of interscapular BAT. This resulted in BAT dysfunction and cold sensitivity but did not predispose the animals to obesity. Interestingly, the loss of brown fat identity due to ablation of Prdm16 was accelerated by concurrent deletion of the closely related Prdm3 gene. Together, these results show that Prdm16 and Prdm3 control postnatal BAT identity and function.
PMCID: PMC4012340  PMID: 24703692
Prdm16; Prdm3; brown fat; brown adipose tissue; obesity; Ucp1; Myf5
9.  Cas Adaptor Proteins Organize the Retinal Ganglion Cell Layer Downstream of Integrin Signaling 
Neuron  2014;81(4):779-786.
Stratification of retinal neuronal cell bodies and lamination of their processes provide a scaffold upon which neural circuits can be built. However, the molecular mechanisms that direct retinal ganglion cells (RGCs) to resolve into a single-cell retinal ganglion cell layer (GCL) are not well understood. The extracellular matrix protein laminin conveys spatial information that instructs the migration, process outgrowth, and reorganization of GCL cells. Here, we show that the β1-Integrin laminin receptor is required for RGC positioning and reorganization into a single-cell GCL layer. β1-Integrin signaling within migrating GCL cells requires Cas signaling-adaptor proteins, and in the absence of β1-Integrin or Cas function retinal neurons form ectopic cell clusters beyond the inner limiting membrane (ILM), phenocopying laminin mutants. These data reveal a novel and essential role for Cas adaptor proteins in β1-Integrin-mediated signaling events critical for the formation of the single-cell GCL in the mammalian retina.
PMCID: PMC3988023  PMID: 24559672
10.  Autoimmune neutropenia preceding Helicobacter pylori-negative MALT lymphoma with nodal dissemination 
Autoimmune neutropenia (AIN), resulting from granulocyte-specific autoantibodies, is much less frequent than other autoimmune hematologic disorders including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). These autoimmune disorders may precede, synchronize, or follow collagen disorders, viral infections, and lymphoid neoplasms. Herein we present the first case of AIN in association with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma with nodal dissemination. In our case, AIN, accompanied by ITP, occurred prior to the clinical manifestation of lymphoma. AIN and ITP were well managed afterwards, but they relapsed in accordance with the recurrence of lymphoma. The administration of prednisolone at 0.5 mg/kg daily alleviated the cytopenias within a week. In general, combination chemotherapy is performed for the treatment of lymphoma-associated autoimmune hematologic disorders and indeed seems to be effective. Our case indicates that corticosteroid monotherapy may be effective for lymphoma-associated AIN especially when AIN precedes the onset of lymphoma.
PMCID: PMC4203267  PMID: 25337296
MALT lymphoma; autoimmune neutropenia; immune thrombocytopenia; corticosteroid; combination chemotherapy
11.  A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice 
Oncogene  2013;33(4):411-420.
Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung, and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9−/− mice compared to MMTV-neu;Nedd9+/+ mice, but instead a dramatic reduction in tumor incidence (18% versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9−/− mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9−/− versus MMTV-neu;Nedd9+/+ mice. The MMTV-neu;Nedd9−/− genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9−/−mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9−/− mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.
PMCID: PMC3628996  PMID: 23318423
breast cancer; HER2; mammary precursor cells; drug resistance
12.  Dynamic Metabolic Changes during the First 3 Months after 90Y-Ibritumomab Tiuxetan Radioimmunotherapy 
The Scientific World Journal  2014;2014:368947.
Objective. To elucidate the time course of tumor metabolism during the first 3 months after 90Y-ibritumomab tiuxetan radioimmunotherapy (RIT) in patients with refractory malignant lymphoma. Materials and Methods. Seven patients with recurrent follicular lymphoma underwent FDG-PET imaging before and after 1-, 4-, and 12-week RIT with 90Y-ibritumomab tiuxetan. Tumor metabolic activity on FDG-PET scans was assessed as the maximum standard uptake value (SUVmax). Results. Decrease in metabolism was detected 1 week after RIT. In the most decreased lesion, SUVmax decreased to 20% of the baseline value during the first week. Most lesions continued to decrease for up to 4 weeks. Some lesions showed increased metabolism from 4 to 12 weeks, while the level of FDG accumulations at 12 weeks was still lower than the baseline. Conclusions. Tumor response to RIT could be observed as early as 1 week after the administration of RIT. After tumor activity decreases, the metabolism may increase at least between 4 and 12 weeks. It suggests that the metabolic changes should be carefully evaluated during this period.
PMCID: PMC4090517  PMID: 25050390
13.  Pulmonary mucormycosis with embolism: two autopsied cases of acute myeloid leukemia 
Mucormycosis is an increasingly important cause of morbidity and mortality for patients with hematological malignancies. The diagnosis of mucormycosis usually requires mycological evidence through tissue biopsy or autopsy because the signs and symptoms are nonspecific and there are currently no biomarkers to identify the disease. We herein present two autopsied cases of acute myeloid leukemia with prolonged neutropenia who developed invasive mucormycosis accompanied by pulmonary artery embolism. Our cases were featured by unexplained fever and rapidly progressive dyspnea. Computed tomography scan detected nodular lesions or nonspecific consolidations in the lungs. Cultures, cytological study, and serum fungal markers consistently gave negative results. Autopsy revealed embolism of the pulmonary artery which consisted of fibrin clots by filamentous fungi. Genomic DNA was extracted from the paraffin-embedded clots and was applied to polymerase chain reaction amplification, leading to the diagnosis of infection by Rhizopus microsporus. We should carefully search for life-threatening pulmonary embolism when patients with hematological malignancies develop pulmonary mucormycosis.
PMCID: PMC4097268  PMID: 25031775
Rhizopus microsporus; mucormycosis; pulmonary embolism; acute myeloid leukemia; neutropenia
14.  Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16 
Cancer Science  2014;105(5):512-519.
Leukemia stem cells (LSC) are resistant to conventional chemotherapy and persistent LSC after chemotherapy are supposed to be a major cause of relapse. However, information on genetic or epigenetic regulation of stem cell properties is still limited and LSC-targeted drugs have scarcely been identified. Epigenetic regulators are associated with many cellular processes including maintenance of stem cells. Of note are polycomb group proteins, because they potentially control stemness, and can be pharmacologically targeted by a selective inhibitor (DZNep). Therefore, we investigated the therapeutic potential of EZH2 inhibition in mixed lineage leukemia (MLL) fusion leukemia. Intriguingly, EZH2 inhibition by DZNep or shRNA not only suppressed MLL fusion leukemia proliferation but also reduced leukemia initiating cells (LIC) frequency. Expression analysis suggested that p16 upregulation was responsible for LICs reduction. Knockdown of p16 canceled the survival advantage of mice treated with DZNep. Chromatin immunoprecipitation assays demonstrated that EZH2 was highly enriched around the transcription-start-site of p16, together with H3K27 methylation marks in MLL/ENL and Hoxa9/Meis1 transduced cells but not in E2A/HLF transduced cells. Although high expression of Hoxa9 in MLL fusion leukemia is supposed to be responsible for the recruitment of EZH2, our data also suggest that there may be some other mechanisms independent of Hoxa9 activation to suppress p16 expression, because expression levels of Hoxa9 and p16 were not inversely related between MLL/ENL and Hoxa9/Meis1 transduced cells. In summary, our findings show that EZH2 is a potential therapeutic target of MLL fusion leukemia stem cells.
PMCID: PMC4317832  PMID: 24612037
3-Deazaneplanocin; histones; homeobox proteins; mixed-lineage acute leukemias; polycomb repressive complex 2
15.  Esophageal intramucosal hematoma after peripheral blood stem cell transplantation: case report and review of literature 
Esophageal complications occur after hematopoietic stem cell transplantation (HSCT). There are, however, only limited reports on the etiology or management of esophageal complications. Here, we report the occurrence of intramucosal hematoma presenting continuous esophageal hemorrhage in a 34 year-old man following the second peripheral blood stem cell transplantation for acute myeloid leukemia. His hematemesis started 2 months after HSCT and was repeated in supportive care. On day 156, he underwent total esophagectomy as a result of uncontrollable massive hematemesis. Histopathological testings of the resected esophagus confirmed intramucosal hematoma as a cause of hematemesis. This case highlights intramucosal hematoma as one of the important etiologies of esophageal complications following HSCT.
PMCID: PMC4069927  PMID: 24966988
Esophageal hemorrhage; intramucosal hematoma; esophagectomy; hematopoietic stem cell transplantation
16.  Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity 
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.
PMCID: PMC3904603  PMID: 24382349
17.  HIV-associated Burkitt lymphoma in a Japanese patient with early submandibular swelling 
BMC Research Notes  2013;6:557.
Patients infected with the human immunodeficiency virus (HIV) are at risk of developing malignancies and have an increased susceptibility to infection. HIV-associated Burkitt lymphoma (BL) is relatively rare in developed countries, but remains prevalent in developing counties and is sometimes compounded by the fact that patients may be unaware that they are HIV-positive.
Case presentation
A 37-year-old Japanese man was referred to our department for diagnosis and management of submandibular swelling. He was unaware that he was HIV-positive at the initial visit. Here, we describe our diagnostic approach, in which we used hematological and immunological investigations, biopsy, fluorescence-activated cell sorting and fluorescence in situ hybridization to confirm the diagnosis of HIV-associated BL. The patient has no risk factors for HIV infection, and the source of infection remains unclear.
In this case, submandibular swelling was the first clinical sign of pathology and the patient’s HIV-positive status only became evident later. It is highly likely that BL was triggered by HIV infection.
PMCID: PMC3877969  PMID: 24370065
Burkitt lymphoma; HIV; Submandibular swelling
18.  Transformation of follicular lymphoma in the retroperitoneal muscles demonstrated by CT-guided needle biopsy of FDG-avid lesions; case series 
We herein report two cases of relapsed follicular lymphoma (FL) with transformation in the retroperitoneal muscles. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT) showed high uptakes in the retroperitoneal muscles. We considered excisional biopsy at first, since it is definitely the most reliable means to obtain histological diagnosis. However, excisional biopsy of the retroperitoneal muscles is challenging for anatomical reasons. Moreover, our patients were kept under poor performance status. Thus, CT-guided percutaneous needle biopsy of FDG-avid retroperitoneal muscles was performed. Histopathological examination of the biopsied specimens demonstrated proliferation of transformed large B cells in both cases. Sheets of large B cells were also recorded in one case. CT-guided needle biopsy is less prioritized than excisional biopsy because of limited information on tissue architecture and increasingly complicated WHO classification. Our series indicate that image-guided needle biopsy of FDG-avid lesions is sufficient for the diagnosis of transformation. Higher priority should be given to this method in the setting of transformed aggressive lymphoma.
PMCID: PMC3885497  PMID: 24427363
Follicular lymphoma; transformation; retroperitoneum; FDG-avid; CT-guided needle biopsy
20.  Eleven secondary cancers after hematopoietic stem cell transplantation using a total body irradiation-based regimen in 370 consecutive pediatric and adult patients 
SpringerPlus  2013;2(1):424.
About the bone marrow transplantation that high dose chemotherapy and total-body irradiation (TBI) are used for as conditioning regimen, a late toxicity may become the problem in the long-term survival patient. One of the toxicities which has been implied to be associated with TBI is secondary cacinogenesis. Between June 1995 and December 2010, 370 patients who were undergoing allogeneic hematopoietic stem cell transplantation using a TBI-based regimen at our department, were the subjects of this study. Eleven secondary cancers occurred in 10 patients. The median time from transplantation to diagnosis of a secondary cancer was 6.8 years. In this analysis, the cumulative incidence rate of secondary cancer at 5 and 10 years was 2.15% and 6.46%, respectively after TBI in our institution.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-2-424) contains supplementary material, which is available to authorized users.
PMCID: PMC3769541  PMID: 24040584
Total body irradiation; Secondary cancer; Bone marrow transplantation
21.  Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells 
The Journal of Clinical Investigation  2013;123(9):3876-3888.
RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.
PMCID: PMC3754260  PMID: 23979164
22.  Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation 
We report here a 47-year-old male with the diagnosis of high-grade B-cell lymphoma and hemophagocytosis accompanying disseminated intravascular coagulation (DIC). Lymphoma-associated hemophagocytic syndrome (LAHS) is a life-threatening disorder, and LAHS secondary to B-cell lymphoma is relatively rare compared to that secondary to T- or NK/T-cell lymphoma in Western countries. T- or NK/T-cell LAHS is sometimes combined with DIC, which makes patients’ outcomes even worse, but few reports of B-cell LAHS accompanying DIC has been published so far. We successfully treated a patient with this condition with recombinant thrombomodulin (rTM), a novel agent for DIC. We believe that rTM is a therapeutic option in cases with B-cell LAHS accompanying DIC.
PMCID: PMC3657377  PMID: 23696942
B-cell lymphoma; lymphoma-associated hemophagocytic syndrome; disseminated intravascular coagulation; recombinant thrombomodulin
23.  Acute myeloid leukemia with cryptic CBFB-MYH11 type D 
A 77 year-old female was found with FAB M4Eo acute myeloid leukemia. Although CBFB-MYH11 mRNA was detected in RT-PCR, the conventional cytogenetic analysis failed to reveal inv(16). Fluorescence in situ hybridization (FISH) and the sequence analysis revealed a fusion between the exon 5 of CBFB and the exon 8 of MYH11, resulting in a minor variant fusion product previously reported as type D. In order to detect the cryptic inv(16) type D, both FISH and RT-PCR are required, and furthermore, the primers for the sequence analysis needs to be selected for the proper diagnosis.
PMCID: PMC3515980  PMID: 23236551
Acute myeloid leukemia; inversion 16; CBFB-MYH11; RT-PCR; fluorescence in situ hybridization
24.  Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity 
The Journal of Experimental Medicine  2011;208(12):2403-2416.
A new mouse in which an IRES-GFP cassette is knocked-in to the Evi1 locus reveals that HSC long-term multilineage repopulating activity specifically segregates with expression of the Evi1 transcription factor.
Ecotropic viral integration site 1 (Evi1), a transcription factor of the SET/PR domain protein family, is essential for the maintenance of hematopoietic stem cells (HSCs) in mice and is overexpressed in several myeloid malignancies. Here, we generate reporter mice in which an internal ribosome entry site (IRES)-GFP cassette is knocked-in to the Evi1 locus. Using these mice, we find that Evi1 is predominantly expressed in long-term HSCs (LT-HSCs) in adult bone marrow, and in the hematopoietic stem/progenitor fraction in the aorta-gonad-mesonephros, placenta, and fetal liver of embryos. In both fetal and adult hematopoietic systems, Evi1 expression marks cells with long-term multilineage repopulating activity. When combined with conventional HSC surface markers, sorting according to Evi1 expression markedly enhances purification of cells with HSC activity. Evi1 heterozygosity leads to marked impairment of the self-renewal capacity of LT-HSCs, whereas overexpression of Evi1 suppresses differentiation and boosts self-renewal activity. Reintroduction of Evi1, but not Mds1-Evi1, rescues the HSC defects caused by Evi1 heterozygosity. Thus, in addition to documenting a specific relationship between Evi1 expression and HSC self-renewal activity, these findings highlight the utility of Evi1-IRES-GFP reporter mice for the identification and sorting of functional HSCs.
PMCID: PMC3256960  PMID: 22084405
25.  Evi1 forms a bridge between the epigenetic machinery and signaling pathways 
Oncotarget  2011;2(7):575-586.
Recent studies have demonstrated the significance of the leukemia oncogene Evi1 as the regulator of hematopoietic stem cells and marker of poor clinical outcomes in myeloid malignancies. Evi1-mediated leukemogenic activities include a wide array of functions such as the induction of epigenetic modifications, transcriptional control, and regulation of signaling pathways. We have recently succeeded in comprehensively elucidating the oncogenic function of Evi1 in a model of the polycomb-Evi1-PTEN/AKT/mTOR axis. These results may provide us with novel therapeutic approaches to conquer the poor prognosis associated with Evi1-activated leukemia or other solid tumors with high Evi1 expression. Here, we review the current understanding of the role of Evi1 in controlling the development of leukemia and highlight potential modalities for targeting factors involved in Evi1-regulated signaling.
PMCID: PMC3248179  PMID: 21795762
Evi1; Leukemia; Polycomb; PTEN; Rapamycin

Results 1-25 (31)