scholarly journals Acute Myeloid Leukemia Driven by the CALM-AF10 Fusion Gene is Dependent on BMI1

2019 ◽  
Author(s):  
Karina Barbosa ◽  
Anwesha Ghosh ◽  
Anagha Deshpande ◽  
Bo-Rui Chen ◽  
Younguk Sun ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Clinical Development ◽  
Molecular Pathways ◽  
Lymphoid Leukemia ◽  
Therapeutic Targeting ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Polycomb Repressive Complex 1 ◽  
Acute Myeloid

ABSTRACTA subset of acute myeloid and lymphoid leukemia cases harbor a t(10;11)(p13;q14) translocation resulting in the CALM-AF10 fusion gene. Standard chemotherapeutic strategies are often ineffective in treating patients with CALM-AF10 fusions. Hence, there is an urgent need to identify molecular pathways dysregulated in CALM-AF10-positive leukemias which may lay the foundation for novel targeted therapies. Here we demonstrate that the Polycomb Repressive Complex 1 gene BMI1 is consistently overexpressed in adult and pediatric CALM-AF10-positive leukemias. We demonstrate that genetic Bmi1 depletion abrogates CALM-AF10-mediated transformation of murine hematopoietic stem and progenitor cells (HSPCs). Furthermore, CALM-AF10-positive murine and human AML cells are profoundly sensitive to the small-molecule BMI1 inhibitor PTC209 as well as to PTC596, a compound in clinical development that has been shown to result in downstream degradation of BMI1 protein. PTC-596 significantly prolongs survival of mice injected with a human CALM-AF10 cell line in a xenograft assay. In summary, these results validate BMI1 as a bonafide candidate for therapeutic targeting in AML with CALM-AF10 rearrangements.

scholarly journals Quantitative proteomics reveals specific metabolic features of acute myeloid leukemia stem cells

Blood ◽  
2020 ◽  
Vol 136 (13) ◽  
pp. 1507-1519 ◽  
Author(s):  
Simon Raffel ◽  
Daniel Klimmeck ◽  
Mattia Falcone ◽  
Aykut Demir ◽  
Alireza Pouya ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Transcript Level ◽  
Characteristic Energy ◽  
Hematopoietic Stem ◽  
Improve Patient Survival ◽  
Stem And Progenitor Cells ◽  
Blast Cells ◽  
Acute Myeloid

Abstract Acute myeloid leukemia is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Because this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus information about posttranscriptionally regulated genes and associated networks is lacking. Here, we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provide strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA-processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts, and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.

A NUP98-HOXD13 Fusion Gene Induces a Transplantable Myelodysplastic Syndrome in Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 401-401
Author(s):  
Yang Jo Chung ◽  
Chul Won Choi ◽  
Christopher Slape ◽  
Terry Fry ◽  
Peter D. Aplan
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Acute Myeloid

Abstract The myelodysplastic syndromes (MDSs) are a group of hematologic stem cell disorders characterized by ineffective hematopoiesis and dysplasia. A large number of chromosomal aberrations including deletions, amplifications, inversions, and translocations, some of which involve the NUP98 gene, have been associated with MDS. Recently an MDS mouse model expressing a NUP98-HOXD13 (NHD13) fusion gene was developed, which faithfully recapitulates all of the key features of MDS. Although it is well-established that acute myeloid leukemia (AML) is transplantable, there is no evidence that MDS is a transplantable condition. Therefore, in order to develop evidence for MDS as a hematopoietic stem cell (HSC) disease, we attempted to transfer MDS to normal recipients through bone marrow transplantation (BMT). All the recipients transplanted with bone marrow (BM) cells from NHD13 mice with MDS showed anemia, leukopenia, lymphopenia, and neutropenia when compared to recipients of wild-type (WT) littermates. The homing efficiency of the NHD13 primitive progenitor cells (Lineage negative [Lin−], Sca-1+) was about 2 fold higher than WT, and there was no significant difference in BM cellularity between the recipients of NHD13 and WT BM, indicating that the NHD13 recipients had ineffective hematopoiesis. These phenomena were reproduced in secondary recipients using primary recipients of NHD13 BM as donor mice. In secondary transplantation assays, 3 out of 5 recipients developed acute myeloid leukemia (AML) at 16 weeks post-transplantation. Morphological features of MDS, including nuclear-cytoplasmic asynchrony, binucleate cells, hypersegmented neutrophils, and giant platelets were detected in BM and peripheral blood of NHD13 donor, primary and secondary recipients by cytospin preparations. In competitive repopulation assays, mice transplanted with equal numbers of WT and NHD13 BM cells showed a decreased percentage of NHD13 cells in the peripheral blood, but an increased percentage of NHD13 cells in the BM, again providing evidence of ineffective hematopoiesis of the NHD13 cells. The transplantation of lineage depleted cells from BM has shown that the transplantable cells for MDS reside in the Lin− population of NHD13 BM. These findings demonstrate that MDS can be transferred to healthy recipients by BMT, supporting the concept that MDS originates in a transplantable multilineage hematopoietic stem cell.

DEK/NUP214 Fusion Gene Predicts Good Outcome In Acute Myeloid Leukemia In Complete Remission After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2386-2386
Author(s):  
Ken Ishiyama ◽  
Akiyoshi Takami ◽  
Shinji Nakao ◽  
Michihiro Hidaka ◽  
Tetsuo Maeda ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Normal Karyotype ◽  
Chromosome 7 ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 2386 Introduction Acute myeloid leukemia (AML) with chromosomal translocation (6;9)(p23;q34) results in a chimeric fusion gene between DEK/NUP214 (formerly DEK/CAN), and is a rare disease, accounting for approximately 1% of cases. This entity is considered to be a good indication for allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to its poor prognosis and non-responsiveness to chemotherapy. However, whether the prognosis of patients with exclusive DEK/NUP214 abnormality is improved by allo-HSCT has not been demonstrated. We conducted a retrospective study to examine the outcomes of allo-HSCT in AML patients with the DEK/NUP214 gene using the databases of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the Japan Cord Blood Bank Network (JCBBN). Methods We identified de novo AML patients who underwent transplant between January 1996 and December 2007 with no prior treatment by allo-HSCT. Clinical features and outcomes of the patients with DEK/NUP214 abnormality and 3 different control groups (patients with chromosome 7 abnormalities, complex karyotype or normal karyotype) were compared. Results Of 4517 AML cases meeting the above criteria, the number of patients with normal karyotype, chromosome 7 abnormalities, complex karyotype and DEK/NUP214 abnormality was 2227, 139, 416 and 64, respectively. The median age of each group was 41, 37, 41 and 34 years, respectively; patients with the DEC/NUP214 abnormality were significantly younger than those with the complex karyotype, and patients with normal chromosomes. Gender was not biased among the groups. Overall survival (OS) of the patients with DEC/NUP214 abnormality at 5 years was 49%, which was superior to the OS of the patients with normal karyotype, chromosome 7 abnormalities and complex karyotype (44%, 30% and 27%, respectively; P < 0.0001; Figure). This trend was significant in HSCT grafts with bone marrow and peripheral blood stem cells. In patients with DEK/NUP214 abnormality, none of the following factors improved survival; combination of gender between patient-donor, dose of total body irradiation prior to HSCT; and use of prophylactic immunosuppressants for graft-versus-host disease. However, the status at HSCT had a significant impact on outcome (5-year OS: 66% in patients in complete remission (CR) at HSCT vs. 31% in non-CR patients; P < 0.001). Analysis exclusively for the patients in CR at HSCT showed similar results as above. Conclusion Our results suggest that patients with the DEK/NUP214 abnormality are more likely to respond to allo-HSCT. Allo-HSCT should be particularly recommended for patients experiencing CR after prior remission-induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals First case report of a NUP98-PMX1 rearrangement in de novo acute myeloid leukemia and literature review

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Weijia Fu ◽  
Aijie Huang ◽  
Hui Cheng ◽  
Yanrong Luo ◽  
Lei Gao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Fusion Gene ◽  
High Dose ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
First Report ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background The nucleoporin 98 (NUP98)-paired related homeobox 1 (PMX1) fusion gene, which results from t(1;11)(q23;p15), is rare in patients with acute myeloid leukemia (AML). Currently, only two cases of chronic myeloid leukemia in the accelerated phase or blast crisis and three cases of therapy-related AML have been reported. Here, we first report a patient with de novo AML carrying the NUP98-PMX1 fusion gene. Case presentation A 49-year-old man diagnosed with AML presented the karyotype 46,XY,t(1;11)(q23;p15)[20] in bone marrow (BM) cells. Fluorescence in situ hybridization analysis using dual-color break-apart probes showed the typical signal pattern. Reverse transcription-polymerase chain reaction (RT-PCR) analysis suggested the presence of the NUP98-PMX1 fusion transcript. The patient received idarubicin and cytarabine as induction chemotherapy. After 3 weeks, the BM aspirate showed complete remission, and the RT-PCR result for the NUP98-PMX1 fusion gene was negative. Subsequently, the patient received three cycles of high-dose Ara-c as consolidation chemotherapy, after which he underwent partially matched (human leukocyte antigen–DP locus mismatch) unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The follow-up period ended on September 30, 2020 (6 months after HSCT), and the patient exhibited no recurrence or transplantation-related complications. Conclusion This is the first report of a patient with de novo AML carrying the NUP98-PMX1 fusion gene. The reported case may contribute to a more comprehensive profile of the NUP98-PMX1 rearrangement, but mechanistic studies are warranted to fully understand the role of this fusion gene in leukemia pathogenesis.

scholarly journals Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Angelica Trujillo ◽  
Christie McGee ◽  
Christopher R. Cogle
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Treatment Strategies ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Autocrine Stimulation ◽  
Novel Treatment Strategies ◽  
Relapsed Disease ◽  
Acute Myeloid

Acute myeloid leukemia (AML) arises from neoplastic transformation of hematopoietic stem and progenitor cells, and relapsed disease remains one of the greater challenges in treating this hematologic malignancy. This paper focuses on angiogenic aspects of AML including the significance and prognostic value of bone marrow microvessel density and circulating cytokine levels. We show three general mechanisms whereby AML exploits angiogenic pathways, including direct induction of angiogenesis, paracrine regulation, and autocrine stimulation. We also present early evidence that leukemia cells contribute directly to vascular endothelia. Novel treatment strategies are proposed, and a review of relevant antiangiogenic clinical trials is presented. By understanding how blood vessels can serve as a reservoir for refractory and relapsed AML, new diagnostics and promising treatment strategies can be developed.

scholarly journals Pathogenic Roles of S100A8 and S100A9 Proteins in Acute Myeloid and Lymphoid Leukemia: Clinical and Therapeutic Impacts

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1323
Author(s):  
Julie Mondet ◽  
Simon Chevalier ◽  
Pascal Mossuz
Keyword(s):  
Immune Regulation ◽  
Leukemic Cells ◽  
Treatment Efficiency ◽  
Lymphoid Leukemia ◽  
Acute Leukemias ◽  
Therapeutic Targeting ◽  
Hematopoietic Stem ◽  
Improve Treatment ◽  
Biologic Effects ◽  
Acute Myeloid

Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). These deregulations impact the prognosis of patients through various mechanisms of cellular or extracellular regulation of the viability of leukemic cells. In particular, S100A8 and S100A9 in monomeric, homodimeric, or heterodimeric forms are able to modulate the survival and the sensitivity to chemotherapy of leukemic clones through their action on the regulation of intracellular calcium, on oxidative stress, on the activation of apoptosis, and thanks to their implications, on cell death regulation by autophagy and pyroptosis. Moreover, biologic effects of S100A8/9 via both TLR4 and RAGE on hematopoietic stem cells contribute to the selection and expansion of leukemic clones by excretion of proinflammatory cytokines and/or immune regulation. Hence, the therapeutic targeting of S100A8 and S100A9 appears to be a promising way to improve treatment efficiency in acute leukemias.

scholarly journals The metalloproteinase inhibitor Prinomastat reduces AML growth, prevents stem cell loss and improves chemotherapy effectiveness

2020 ◽  
Author(s):  
Chiara Pirillo ◽  
Myriam Haltalli ◽  
Sara Gonzalez Anton ◽  
Valentina Tini ◽  
Isabella Kong ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Therapeutic Potential ◽  
Cell Loss ◽  
Complementary Therapy ◽  
Human Leukemia ◽  
Hematopoietic Stem ◽  
Healthy Cell ◽  
Mmp Inhibitor ◽  
Stem And Progenitor Cells ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias, linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanism behind HSPC decline is complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Numerous human leukemia types, particularly MLL-AF9 samples, show high expression levels of multiple matrix metalloproteinases (MMPs). Therefore, we evaluate the therapeutic potential of the MMP inhibitor (MMPI) prinomastat. IVM analyses of treated mice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML cell speed. Furthermore, treated mice have decreased BM infiltration, increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Overall, our results suggest that MMPIs could be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.

Gain-of-Function Mutations of GATA-2 in Acute Myeloid Transformation of Chronic Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1022-1022
Author(s):  
Su-Jiang Zhang ◽  
Li-Yuan Ma ◽  
Qiu-Hua Huang ◽  
Guo Li ◽  
Bai-Wei Gu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Negative Regulator ◽  
Blast Transformation ◽  
Monocytic Differentiation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Acquisition of additional genetic and/or epigenetic abnormalities other than BCR/ABL fusion gene is believed to cause disease progression in chronic myeloid leukemia (CML) from chronic phase to blast phase. To gain insights into the underlying mechanisms, we screened DNA samples from CML patients during acute transformation for alterations in a number of transcription factor genes crucial to myeloid-lymphoid development. In 85 cases of CML blast transformation, we identified two new mutations in the coding region of GATA-2, a negative regulator of hematopoietic stem/progenitor cell differentiation. L359V within zinc finger domain (ZF) 2 of GATA-2 was found in 8 cases with myelo-monoblastic features, while an in-frame deletion of six amino acids (D341–346) across the border of ZF1 was detected in 1 patient at blast crisis with eosinophilia. Further studies showed that L359V not only increased transactivation activity, but also enhanced inhibitory effects on the major myelopoietic regulator PU.1. Consistent with the myelo-monoblastic features of CML patients with GATA-2 L359V mutant, transduction of GATA-2 L359V mutant into HL-60 cells or BCR/ABL-harboring mouse model disturbed myelo-monocytic differentiation/proliferation in vitro and in vivo, respectively. These data suggest that GATA-2 mutations may be involved in acute myeloid transformation in some CML patients.

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