Mcm2 Deficiency Leads to Bone Marrow Failure and Lymphoid Malignancies Dependent on Age and Genetic Background

Abstract DNA replicative stress is associated with malignant transformation. Mini-chromosome maintenance 2 (hereafter Mcm2) is a component of the DNA helicase complex that plays a pivotal role in DNA replication. The Mcm2-7 complex is loaded onto chromatin during the G1-phase of the cell cycle and is required for initiation of DNA replication in the subsequent S-phase. Mice with a Cre cassette inserted into the 3'UTR of the Mcm2 gene (designated Mcm2 Cre) were generated as a tool to assess Mcm2 expression. Unexpectedly, mice with two copies of this allele (Mcm2 Cre/Cre) had decreased expression of Mcm2 protein (~20-30% of the wild type (WT) expression level), likely due to decreased RNA stability caused by insertion of the Cre cassette. Surprisingly, all Mcm2 Cre/Cre mice developed a lethal pre-T lymphoblastic leukemia/lymphoma (pre-T LBL) with a median survival of under 3 months. These pre-T LBL were characterized by 10-20 interstitial deletions of approximately 50-1000 kb, often involving genes known to be mutated or deleted in human pre-T LBL, such as Notch1, Pten, Tcf3, and Cdkn2a. Thus, Mcm2 Cre/Cre mice display a novel mutator/deletor phenotype that results in malignant transformation. Although the Mcm2 hypomorph is a germline defect, the malignancies we identified in Mcm2 Cre/Cre mice were restricted to thymocytes. We hypothesized that Mcm2 Cre/Cre mice were susceptible to non-thymocyte malignancies, but due to the early onset of pre-T LBL (within 4 months of age), these putative non-thymocyte malignancies did not have an opportunity to develop. We transplanted Mcm2 Cre/Cre Lin-Sca-1+Kit+ (LSK) hematopoietic stem/progenitor cells (HSPCs) isolated from 5-week-old Mcm2 Cre/Cre bone marrow into WT recipients, which led to marked anemia and thrombocytopenia without evidence of leukemic transformation at 5 months post-transplant. Consistent with this finding, bone marrow from 5-week-old Mcm2 Cre/Cre mice also showed decreased LSK and Lin-Sca-1-Kit+ (LK) cells compared to WT mice, suggesting that the bone marrow failure was uncovered by the more prolonged survival of Mcm2 Cre/Cre LSK recipients vs. non-transplanted Mcm2 Cre/Cre mice (5 mos. vs. <3 mos.) . As an alternate approach to preventing pre-T LBL, we crossed the Mcm2 Cre allele onto a nude (nu/nu) background, as nude mice lack thymic epithelial cells, preventing T cell development. Mcm2 Cre/Cre nu/nu mice had markedly prolonged survival compared to Mcm2 Cre/Cre (median 296.5 vs. 80.5 days, respectively; P < 0.0001). Most of the Mcm2 Cre/Cre nu/nu mice succumbed to B-cell precursor acute lymphoblastic leukemia (BCP-ALL) within 10 months of life. To determine whether Mcm2 Cre/Cre nu/nu would develop acute myeloid leukemia (AML) if placed on myeloid leukemia sensitized background, we crossed Mcm2 Cre/Cre nu/nu mice with mice expressing a NUP98-PHF23 (NP23) transgene, as the NP23 fusion gene predisposes mice to develop AML. All Mcm2 Cre/Cre nu/nu NP23 mice died within 5 months of age, primarily due to BCP-ALL. Sparse whole-genome sequencing (WGS) was used to detect copy number aberration (CNA), and we identified recurrent deletions of 100-1000 kb that involved genes known or suspected to be involved in BCP-ALL, including Pax5, Ikzf3, Il7r, and Bcor. Whole-exome sequencing identified recurrent mutations, Jak1/Jak3, Ptpn11, and Kras. In an effort to identify 100-1000 kb interstitial deletions in non-hematopoietic tissue, we used sparse WGS to identify CNA in single-cell cloned mouse embryo fibroblasts (MEF) from Mcm2 Cre/Cre, Mcm2 Cre/Wt, and Mcm2 Wt/Wt mice. Very few CNAs were identified in any of the MEFs. We conclude that this unique deletor phenotype found in Mcm2 Cre/Cre mice is a powerful tool for the identification of tumor suppressor genes in lymphoid leukemia, and that B- and T- lymphocytes are uniquely susceptible to this deletor phenotype. Disclosures No relevant conflicts of interest to declare.

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Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

Blood Advances ◽

10.1182/bloodadvances.2020001541 ◽

2020 ◽

Vol 4 (21) ◽

pp. 5540-5546

Author(s):

Laurent Schmied ◽

Patricia A. Olofsen ◽

Pontus Lundberg ◽

Alexandar Tzankov ◽

Martina Kleber ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Driver Mutations ◽

Leukemic Transformation ◽

Hematopoietic Stem ◽

Bone Marrow Failure Syndromes ◽

Proinflammatory Responses ◽

Stem And Progenitor Cells

Abstract Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

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Paroxysmal Nocturnal Hemoglobinuria with a Distinct Molecular Signature Diagnosed Ten Years after Allogenic Bone Marrow Transplantation for Acute Myeloid Leukemia

Case Reports in Hematology ◽

10.1155/2019/8928623 ◽

2019 ◽

Vol 2019 ◽

pp. 1-3

Author(s):

Alberto Santagostino ◽

Laura Lombardi ◽

Gerard Dine ◽

Pierre Hirsch ◽

Srimanta Chandra Misra

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Somatic Mutation ◽

Myeloid Leukemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Clonal Selection ◽

Bone Marrow Failure ◽

Clinical Manifestations ◽

Hematopoietic Stem ◽

Acute Myeloid

Paroxysmal nocturnal hemoglobinurea (PNH) is a rare disorder of complement regulation due to somatic mutation of PIGA (phosphatidylinositol glycan anchor) gene. We herewith report a case who developed a symptomatic PNH long after an allogenic marrow transplant. Some reasonable arguments concerning the origin of PNH clone have been discussed. The molecular studies revealed presence of JAK2 and TET2 mutations without a BCOR mutation. The literature review has been performed to probe into the complex interplay of autoimmunity and clonal selection and expansion of PNH cells, which occurs early in hematopoietic differentiation. The consequent events such as hypoplastic and/or hemato-oncologic features could further be explained on the basis of next-generation sequencing (NGS) studies. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder of hematopoietic stem cells, characterized by a somatic mutation of the phosphatidylinositol glycan-class A (PIGA). The PIGA gene products are crucial for biosynthesis of glycosylphosphatidylinositol (GPI) anchors, which attaches a number of proteins to the plasma membrane of the cell. Amongst these proteins, the CD55 and CD59 are complement regulatory proteins. The CD55 inhibits C3 convertase whereas the CD59 blocks the membrane attack complex (MAC) by inhibiting the incorporation of C9 to MAC. The loss of complement regulatory protein renders the red cell susceptible to complement-mediated lysis leading to intravascular and extravascular hemolysis. The intravascular hemolysis explains most of the morbid clinical manifestations of the disease. The clinical features of syndrome of PNH are recurrent hemolytic episodes, thrombosis, smooth muscle dystonia, and bone marrow failure; other important complications include renal failure, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). The most used therapies were blood transfusions, immunosuppressive, and steroid. Allogeneic stem cell transplantation was also practiced. At present, the therapy of choice is eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal antibody that blocks activation of the terminal complement at C5. The limiting factor for this therapy is breakthrough hemolysis and the frequent dosing schedule. Ravulizumab (ALXN1210) is the second generation terminal compliment inhibitor which seems to provide a sustained control of hemolysis without breakthrough hemolysis and with a longer dosing interval.

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Acute Lymphoblastic Leukemia in a Patient with Monomac Syndrome/GATA2 Haploinsufficiency

Blood ◽

10.1182/blood.v126.23.3729.3729 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3729-3729

Author(s):

Ashley Koegel ◽

Venee N. Tubman ◽

Inga Hofmann

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Lymphoblastic Leukemia ◽

Killer Cell ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Monosomy 7 ◽

Definitive Therapy

Abstract Background: Heterozygous germline mutations in GATA2 have been described in three distinct conditions: 1) familial myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML), 2) Emberger syndrome which is characterized by lymphedema, warts and predisposition to MDS/AML, 3) MonoMac syndrome which is comprised of atypical nontuberculous mycobacterial infection, monocyte, and B and natural killer cell lymphoid deficiency. It is now recognized that these conditions represent a spectrum of hematopoietic, lymphatic and immune system disorders due to GATA2 haplosinsufficiency. MDS/AML due to GATA2 mutation shows a unique histopathology with characteristic dysplasia and is often associated with monosomy 7. Although many patients with GATA2 haploinsufficiency are initially asymptomatic the majority of patients will ultimately experience a significant complication such as severe infections due to immunodeficiency, pulmonary alveolar proteinosis (PAP), thrombotic events, bone marrow failure, MDS and progression to AML. Allogenic hematopoietic stem cell transplant (HSCT) is the only curative treatment for patients with GATA2 haploinsufficiency and those who develop MDS/AML. Here we report a unique patient who presented with with acute lymphoblastic leukemia (ALL) and was later found to have classical features of MonoMAC syndrome and GATA2 haploinsufficiency. Case Summary: A previously healthy 11 year-old girl presented with fever, cellulitis, and pancytopenia. Bone marrow biopsy and aspirate were diagnostic for B-precursor acute lymphoblastic leukemia (ALL) with associated monosomy 7 and the following karyotype: 45,XX,-7,del(9)(p13),del(10)(q24). She was treated on Dana Farber Cancer Institute (DFCI) Consortium ALL Protocol 05-001, achieving a morphological and cytogenetic remission. During induction, she developed necrotizing aspergillus pneumonia and molluscum contagiousum. Her planned course of therapy was abbreviated due to the development of restrictive lung disease associated with PAP and disseminated Mycobacterium kansasii infection. Serial off therapy bone marrow studies were obtained given poor count recovery and revealed significant morphologic dysplasia, most prominent in the megakaryocytes. These findings were reminiscent of those characteristically seen in patients with GATA2 haploinsufficiency. Her infectious complications, profound monocytopenia, PAP and bone marrow dysplasia raised concern for MonoMAC Syndrome. Sanger Sequencing of GATA2 revealed a point mutation in the regulatory enhancer region of intron 5 (c.1017+572C>T) confirming the diagnosis. More than 3 years following remission of ALL, she developed a bone marrow relapse with her initial clone. Given her diagnosis of GATA2 haploinsufficiency, HSCT was selected as consolidation therapy in second remission. She succumbed to complications of HSCT 4 months after transplantation. Conclusion: Patients with GATA2 haploinsufficiency show a heterogeneous clinical presentation and are at high risk for MDS/AML often associated with monosomy 7. The development of ALL in association with GATA2 haploinsufficiency has not been described in the literature. Hematologist and oncologists should be aware that ALL may be associated with GATA2 haploinsufficiency and should be attuned to the clinical, laboratory and histopathologic features of the MonoMAC syndrome that would prompt additional testing and potentially alter treatment regimens. As allogenic HSCT is the only definitive therapy for patients with GATA2 mutation, consideration of immediate HSCT following induction of remission should be considered in patients with ALL and GATA2 haploinsufficiency. Further, as patients with GATA2 mutations can be asymptomatic, it is imperative to screen family members for GATA2 mutations and offer genetic counselling prior to consideration as potential bone marrow donors. Disclosures No relevant conflicts of interest to declare.

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Inherited bone marrow failure syndromes: considerations pre- and posttransplant

Hematology ◽

10.1182/asheducation-2017.1.88 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 88-95 ◽

Cited By ~ 14

Author(s):

Blanche P. Alter

Keyword(s):

Bone Marrow ◽

Birth Defects ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Hematopoietic Stem ◽

Diamond Blackfan Anemia ◽

Bone Marrow Failure Syndromes ◽

Shwachman Diamond Syndrome ◽

Generation Sequencing

Abstract Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.

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IL-6 blockade reverses bone marrow failure induced by human acute myeloid leukemia

Science Translational Medicine ◽

10.1126/scitranslmed.aax5104 ◽

2020 ◽

Vol 12 (538) ◽

pp. eaax5104 ◽

Cited By ~ 4

Author(s):

Tian Yi Zhang ◽

Ritika Dutta ◽

Brooks Benard ◽

Feifei Zhao ◽

Raymond Yin ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Xenograft Model ◽

Erythroid Differentiation ◽

Hematopoietic Stem ◽

Human Acute Myeloid Leukemia ◽

Immunocompromised Mice ◽

Acute Myeloid

Most patients with acute myeloid leukemia (AML) die from complications arising from cytopenias resulting from bone marrow (BM) failure. The common presumption among physicians is that AML-induced BM failure is primarily due to overcrowding, yet BM failure is observed even with low burden of disease. Here, we use large clinical datasets to show the lack of correlation between BM blast burden and degree of cytopenias at the time of diagnosis. We develop a splenectomized xenograft model to demonstrate that transplantation of human primary AML into immunocompromised mice recapitulates the human disease course by induction of BM failure via depletion of mouse hematopoietic stem and progenitor populations. Using unbiased approaches, we show that AML-elaborated IL-6 acts to block erythroid differentiation at the proerythroblast stage and that blocking antibodies against human IL-6 can improve AML-induced anemia and prolong overall survival, suggesting a potential therapeutic approach.

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Inherited bone marrow failure syndromes: considerations pre- and posttransplant

Blood ◽

10.1182/blood-2017-05-781799 ◽

2017 ◽

Vol 130 (21) ◽

pp. 2257-2264 ◽

Cited By ~ 23

Author(s):

Blanche P. Alter

Keyword(s):

Bone Marrow ◽

Birth Defects ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Hematopoietic Stem ◽

Diamond Blackfan Anemia ◽

Bone Marrow Failure Syndromes ◽

Shwachman Diamond Syndrome ◽

Generation Sequencing

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Deletion of the p53 Target Gene PUMA Prevents Bone Marrow Failure in a Dyskeratosis Congenita Mouse Model

Blood ◽

10.1182/blood-2018-99-116349 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 648-648

Author(s):

Miriam Erlacher ◽

Christian Molnar ◽

Julia Miriam Weiss ◽

Sheila Bohler ◽

Doris Steinemann ◽

...

Keyword(s):

Bone Marrow ◽

Dna Damage ◽

Mouse Model ◽

Malignant Transformation ◽

Ex Vivo ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Hematopoietic Stem ◽

Apoptosis Pathway ◽

Intrinsic Apoptosis Pathway

Abstract Dyskeratosis congenita (DC) belongs to the group of inherited bone marrow failure syndromes (IBMFS) and is characterized by premature telomere shortening caused by mutations in components of the telomerase or the shelterin complexes. The main cause of death in affected patients is hematopoietic failure, but there is also a 10-15% risk of malignant transformation into secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Critically short telomeres activate a DNA damage response with p53-mediated cell cycle inhibition, senescence and/or apoptosis, the latter mediated primarily by PUMA, a BCL-2 family member belonging to the group of pro-apoptotic BH3-only proteins and transcriptionally regulated by p53. Activation of p53 and expression of its target genes are critical for the exhaustion of hematopoietic stem cells (HSCs) in DC patients. Inactivation of the DNA damage checkpoint could possibly mitigate hematopoietic failure but poses a significant risk of genomic instability and leukemia. Based on our earlier mouse model of secondary leukemia (Genes Dev, 24(15):1602-7), we hypothesized that selective inhibition of p53-mediated apoptosis - while all other p53-checkpoint-induced pathways remain active - could both delay hematopoietic failure and prevent malignant transformation. We established a DC mouse model by serial transplantation of hematopoietic stem and progenitor cells (HSPCs) derived from generation 3 mTerc-/- (G3 mTerc-/-) mice lacking the RNA telomerase component. While 8-12 week old donor mice and primary recipients had only a mild hematopoietic phenotype, secondary recipients demonstrated severe lymphopenia. 41% of secondary recipients died within 50 days after transplantation, and flow cytometric and histological analysis revealed pancytopenia and bone marrow aplasia. The surviving secondary recipients were analyzed 16 weeks after transplantation and displayed severely reduced HSPC viability ex vivo. Aiming to inhibit HSPC apoptosis in vivo, we deleted Puma in G3 mTerc-/- mice. PUMA deficiency significantly rescued bone marrow numbers, HSPC viability ex vivo (72% vs. 50% viable HSPCs, p=0.01) and hematopoietic output on a G3 mTerc-/-background. Most importantly, death of secondary recipients was fully prevented in the absence of PUMA. This rescue is associated with significantly longer telomeres and reduced levels of γH2AX foci in G3 mTerc-/-Puma-/- donor and recipient HSPCs when compared to their PUMA proficient counterparts. Notably, no signs of myelodysplasia or leukemia were found in mice receiving serial transplantations of G3 mTerc-/-Puma-/- bone marrow. Our data indicate that specific inhibition of the intrinsic apoptosis pathway is sufficient to restrain the death of HSPCs with critically short telomeres and ensure blood formation. The resulting reduction of proliferative pressure within the HSPC compartment preserves functional and genetic integrity of HSCs and leads to generally longer telomeres in the HSPC pool. We anticipate that prevention of bone marrow failure is sufficient to prevent outgrowth of (pre)malignant clones and transformation to secondary MDS and AML. Disclosures Niemeyer: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Impaired myelopoiesis in congenital neutropenia: insights into clonal and malignant hematopoiesis

Hematology ◽

10.1182/hematology.2021000286 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 514-520

Author(s):

Julia T. Warren ◽

Daniel C. Link

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Severe Congenital Neutropenia ◽

Congenital Neutropenia ◽

Hematopoietic Stem ◽

Myeloid Malignancy ◽

Bone Marrow Failure Syndromes ◽

Increased Risk ◽

Shwachman Diamond Syndrome

Abstract A common feature of both congenital and acquired forms of bone marrow failure is an increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Indeed, the development of MDS or AML is now the major cause of mortality in patients with congenital neutropenia. Thus, there is a pressing clinical need to develop better strategies to prevent, diagnose early, and treat MDS/AML in patients with congenital neutropenia and other bone marrow failure syndromes. Here, we discuss recent data characterizing clonal hematopoiesis and progression to myeloid malignancy in congenital neutropenia, focusing on severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome. We summarize recent studies showing excellent outcomes after allogenic hematopoietic stem cell transplantation for many (but not all) patients with congenital neutropenia, including patients with SCN with active myeloid malignancy who underwent transplantation. Finally, we discuss how these new data inform the current clinical management of patients with congenital neutropenia.

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Role of CD44 in Endogenous Kras G12D-mediated Myeloproliferative Neoplasm

Blood ◽

10.1182/blood.v118.21.1398.1398 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1398-1398

Author(s):

Juan Du ◽

Yangang Liu ◽

Lixuan Tan ◽

Juinn Cherng Lo ◽

Jinyong Wang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Myeloproliferative Neoplasm ◽

Cytokine Signaling ◽

Hematopoietic Stem ◽

Gm Csf ◽

A Cell

Abstract Abstract 1398 Abstract Oncogenic KRAS mutations are identified in virtually all the cancer types, making KRAS one of the most frequently mutated genes in human cancers. Our lab established a mouse model of myeloproliferative neoplasm (MPN) initiated by oncogenic Kras mutation (Kras G12D) expressed from its endogenous locus. Because CD44, a cell adhesion molecule and a cell signaling regulator, was found to involve in regulating leukemic stem cells in chronic myeloid leukemia (Krause, Lazarides et al. 2006) and acute myeloid leukemia (Jin, Hope et al. 2006), we have generated compound mice expressing oncogenic Kras but deficient for CD44 (Kras G12D; CD44−/−) to examine the role of CD44 in endogenous oncogenic Kras- mediated MPN. Our preliminary data show that loss of CD44 prolonged survival of compound Kras G12D; CD44−/− mice and greatly downregulated GM-CSF signaling in hematopoietic stem/progenitor cells. However, CD44 deficiency did not significantly affect the development of MPN, suggesting that GM-CSF signaling is not essential for Kras G12D-initiated MPN and CD44 deficiency might not affect other cytokine signaling. We are currently investigating this issue. Because Kras G12D hematopoietic stem cells (HSCs) are required to initiate MPN phenotypes, we then examined whether loss of CD44 would affect the behavior of Kras G12D HSCs. Our preliminary results demonstrate that CD44 deficiency did not significantly alter HSC frequencies in bone marrow and spleen, nor their cell cycle profile and apoptosis status. When Kras G12D; CD44−/− bone marrow cells were transplanted into lethally irradiated mice by retro-orbital injection, ∼19% of recipient mice developed MPN, similarly to recipient mice transplanted with same number of Kras G12D cells (∼14%). These MPN mice simultaneously developed acute T-cell lymphoblastic leukemia/lymphoma. Our results suggest that CD44 is dispensable for the homing and engraftment of Kras G12D HSCs. We are currently investigating whether CD44 function is essential for the homing and engraftment of leukemic initiating cells of MPN. Disclosures: No relevant conflicts of interest to declare.

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