Hematopoietic Stem Cell Differentiation Pathway in Humans Deduced From the Lineage Diversity of PNH-Type Cells in Patients with Bone Marrow Failure.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1489-1489
Author(s):  
Takamasa Katagiri ◽  
Zhirong Qi ◽  
Yu Kiyu ◽  
Naomi Sugimori ◽  
J. Luis Espinoza ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Bone Marrow Failure ◽  
Stem Cell Differentiation ◽  
Refractory Anemia ◽  
Hematopoietic Stem

Abstract Abstract 1489 Poster Board I-512 The hematopoietic stem cell (HSC) differentiation pathway in humans remains largely unknown due to the lack of an appropriate in vivo assay allowing the growth of HSCs as well as of clonal markers that enable the tracing of their progenies. Small populations of blood cells deficient in glycosylphosphatidylinositol-anchored proteins (GPI-APs) such as CD55 and CD59 are detectable in approximately 50% of patients with aplastic anemia (AA) and 15% of patients with refractory anemia (RA) of myelodysplastic syndrome defined by the FAB classification. Such blood cells with the paroxysmal nocturnal hemoglobinuria (PNH) phenotype (PNH-type cells) are derived from single PIGA mutant HSCs and their fate depends on the proliferation and self-maintenance properties of the individual HSCs that undergo PIG-A mutation by chance (Blood 2008;112:2160, Br J Haematol 2009 in press) Analyses of the PNH-type cells from a large number of patients on the diversity of lineage combination may help clarify the HSC differentiation pathway in humans because PIG-A mutant HSCs in patients with bone marrow failure appear to reflect the kinetics of healthy HSCs. Therefore, different lineages of peripheral blood cells were examined including glycophorin A+ erythrocytes (E), CD11b+ granulocytes (G), CD33+ monocytes (M), CD3+ T cells (T), CD19+ B cells (B), and NKp46+ NK cells (Nk) from 527 patients with AA or RA for the presence of CD55−CD59− cells in E and G, and CD55−CD59−CD48− cells in M,T, B, Nk with high sensitivity flow cytometry. Two hundred and twenty-eight patients (43%) displayed 0.003% to 99.1% PNH-type cells in at least one lineage of cells. The lineage combination patterns of PNH-type cells in these patients included EGM in 71 patients (31%), EGMTBNk in 43 (19%), EG in 37 (16%), T alone 14 (6%), EGMBNk in 11 (5%), G alone in 10 (4%), GM in 10 (4%), EGMNk in 7 (3%), EGMT in 7 (3%), EGMB in 6 (3%), EM in 5 (2%), EGMTB in 3 (1%), EGNk in 1 (0.4%), EGMTNk in 1 (0.4%), GMTB in 1 (0.4%), and GT in 1 (0.4%) (Table). All patterns included G or M, except for 14 patients displaying PNH-type T cells alone. No patients showed TB or TBNk patterns suggestive of the presence of common lymphoid progenitor cells. Peripheral blood specimens from 123 patients of the 228 patients possessing PNH-type cells were examined again after 3 to 10 months and all patients showed the same combination patterns as those revealed by the first examination. PIG-A gene analyses using sorted PNH-type cells from 3 patients revealed the same mutation in G and Nk for 1 patient and in G and T for 2 patients. These findings indicate that human HSCs may take a similar differentiation pathway to that of murine HSCs, the ‘myeloid-based model’ that was recently proposed by Kawamoto et al. (Nature 2008; 10:452), though the cases with PNH-type T cells alone remain to be elucidated. Table. Lineages of cells containing PNH-type cells in patients with AA or RA. The number in the parenthesis denotes the proportion of patients showing each combination pattern in the total patients possessing PNH-type cells. (+ ; presence of PNH-type cells) Disclosures No relevant conflicts of interest to declare.

scholarly journals CD8 + T cells drive autoimmune hematopoietic stem cell dysfunction and bone marrow failure

2016 ◽  
Vol 75 ◽  
pp. 58-67 ◽  
Author(s):  
David M. Gravano ◽  
Mufadhal Al-Kuhlani ◽  
Dan Davini ◽  
P. Dominick Sanders ◽  
Jennifer O. Manilay ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cd8 T Cells ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Cell Dysfunction

scholarly journals The Role of Macrophages in Bone Marrow Injury and Hematopoietic Reconstitution

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3729-3729
Author(s):  
Wen Ju ◽  
Tiantian Sun ◽  
Wenyi Lu ◽  
Kailin Xu ◽  
Jianlin Qiao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Sublethal Dose ◽  
Hematopoietic Stem

Introduction Successful homing, engrafment and effective hematopoietic recovery after hematopoietic stem cell transplantation (HSCT) are strictly regulated by various hematopoietic microenvironment cells. Increasing evidence shows that macrophages (MФs), one of the most important component niche cells are crucial for the haematopoietic regulation. MФs depletion can enhance hematopoietic stem cell mobilization. Our previous study showed that MФs ameliorate bone marrow inflammatory injury and promote hematopoiesis in mice after allo-HSCT, but its role in syngeneic HSCT and acute bone marrow injury is still unknown. Our aim is to explore the role of macrophages in acute bone marrow injury and hematopoietic reconstitution after isogenic hematopoietic stem cell transplantation and sublethal dose irradiation in vivo. Methods BALB/c male mice at 8-10 weeks were irradiated with 60 Co 7.5 Gy and 3.0 Gy, respectively, and then isogenic hematopoietic stem cell transplantation model and sublethal-dose bone marrow injury model were constructed. The transplantation model mice were randomly divided into total body irradiation group (TBI group), bone marrow cell transplantation group (BMT group), bone marrow cell transplantation + Clodronate Liposomes injection group (BMT+Clod-Lip group), bone marrow cell transplantation + PBS Liposomes injection group ( BMT + PBS-Lip group), and normal control group (Normal group). The sublethal-dose experimental mice were randomly divided into the total body irradiation group (TBI group), the whole body irradiation + Clodronate Liposomes injection group (TBI+Clod-Lip group), the whole body irradiation + PBS Liposomes injection group (TBI+PBS-Lip group), and normal control group (Normal group). Mice in Clod-Lip group were injected with Clodronate Liposomes for several specific times to deplete macrophages until the specimens were obtained. Mice in PBS-Lip group were injected PBS Liposomes as controls.Then, the living conditions and body weight changes of the mice were observed and the survival rates of mice in different experimental groups were recorded. Peripheral blood and bone marrow in each group were collected at the corresponding detection time, blood routine analyzer was used to detect blood routine changes, HE staining was used to observe bone marrow damage, and flow cytometry was used to analyze changes in macrophages, hematopoietic stem/progenitor cells and their subgroups such as myeloid cells, megakaryocytes, and nucleated red blood cells in bone marrow. Results Depletion of bone marrow macrophages could reduce the survival rate of hematopoietic stem cell transplantation mice. The pathological results of bone marrow showed that bone marrow injury were heaviest on the 7th day in all three transplantation groups, and then gradually alleviated. The recovery of the BMT+Clod-Lip group was inferior to that of the BMT+PBS-Lip group and the BMT group at the corresponding time point. Depletion of macrophages increased the percentage of myeloid cells in the bone marrow and the number of white blood cells in the peripheral blood, reduced the total number of bone marrow cells, the proportion of hematopoietic stem cells and megakaryocytes in the bone marrow, and delayed recovery of red blood cells and platelets in peripheral blood; Depletion of bone marrow macrophages could also reduce survival rate of sublethal dose irradiation mice, delayed the repair of pathological damage of bone marrow, and increase the proportion of progenitor cells, CMP, GMP, myeloid cells and the number of peripheral white blood cells ,increase the proportion of hematopoietic stem cell apoptosis, reduce the total number of bone marrow cells, the proportion of hematopoietic stem cells, MEP, megakaryocytes and nucleated red blood cells in the bone marrow, delayed peripheral blood recovery of red blood cells and platelets. Conclusion In the isogenic hematopoietic stem cell transplantation model and the sublethal dose irradiation mouse model, the removal of mouse bone marrow macrophages could affect the survival rate of transplanted mice, aggravate the pathological damage of bone marrow, increase the number of GMP and white blood cells, and reduce the total number of bone marrow cells, the number of hematopoietic stem cells and MEP cells. Macrophage depletion was not conducive to the recovery of peripheral blood red blood cells and platelets. Disclosures No relevant conflicts of interest to declare.

scholarly journals ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH FANCONI ANEMIA.

2016 ◽  
Vol 8 ◽  
pp. 2016054 ◽  
Author(s):  
Hosein Kamranzadeh fumani ◽  
Mohammad Zokaasadi ◽  
Amir Kasaeian ◽  
Kamran Alimoghaddam ◽  
Asadollah Mousavi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Term Survival ◽  
Hematopoietic Stem

Background & objectives: Fanconi anemia (FA) is a rare genetic disorder caused by an impaired DNA repair mechanism which leads to an increased tendency toward malignancies and progressive bone marrow failure. The only curative management available for hematologic abnormalities in FA patients is hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate the role of HSCT in FA patients.Methods: Twenty FA patients with ages of 16 or more who underwent HSCT between 2002 and 2015 enrolled in this study. All transplants were allogeneic and the stem cell source was peripheral blood and all patients had a full HLA-matched donor.Results: Eleven patients were female and 9 male (55% and 45%). Mean age was 24.05 years. Mortality rate was 50% (n=10) and the main cause of death was GVHD. Survival analysis showed an overall 5-year survival of 53.63% and 13 year survival of 45.96 % among patients.Conclusion: HSCT is the only curative management for bone marrow failure in FA patients and despite high rate of mortality and morbidity it seems to be an appropriate treatment with an acceptable long term survival rate for adolescent and adult group.

scholarly journals Detection of Mutations in Inherited Bone Marrow Failure and Myelodysplastic Syndrome Genes Using Genomic Capture and Massively Parallel Sequencing in Clinical Diagnostics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1507-1507
Author(s):  
Siobán B. Keel ◽  
Tom Walsh ◽  
Colin Pritchard ◽  
Akiko Shimamura ◽  
Mary-Claire King ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Genetic Testing ◽  
Hematopoietic Stem Cell ◽  
Copy Number ◽  
Bone Marrow Failure ◽  
Copy Number Variants ◽  
Donor Selection ◽  
Hematopoietic Stem ◽  
Pathogenic Mutations

Abstract Accurate and timely diagnosis of inherited bone marrow failure (BMF) and myelodysplastic syndromes (MDS) ensures appropriate clinical management. The correct diagnosis allows appropriate monitoring for both hematopoietic (i.e. clonal evolution and progressive marrow failure) and extra-hematopoietic complications, informs the timing of hematopoietic stem cell transplant, donor selection and transplant regimen planning, and ensures appropriate genetic counseling of family members. Substantial phenotypic overlap among these disorders and the variable expressivity within syndromes complicate their diagnosis based purely on physical exam and standard laboratory testing and provide the rationale for comprehensive genetic diagnostic testing. We report here our initial one-year experience utilizing a targeted capture assay of known inherited BMF/MDS genes for clinical diagnostic purposes at the University of Washington. The assay sequences all exons and 20 base pairs of intronic sequence flanking each exon, as well as several regulatory and intronic regions of specific genes containing known pathogenic variants of 85 known inherited BMF/MDS genes (Zhang M. et al. Haematologica 2016). Between June 2015 and July 2016, 81 individual patients were referred for clinical testing (median age: 15 years-old, range: 0.6-76 years-old). For all samples evaluated, median coverage across the 383kb targeted region was 1887X. This depth of coverage enabled identification of all classes of mutations, including point mutations, small indels, copy number variants, and genomic rearrangements. Pathologic mutations in known inherited BMF/MDS genes were identified in 12 of 82 (14.6%) individuals (median age 13 years-old, range: 1.25-43 years-old) across a broad number of genes and of multiple classes including copy number variants (Table). Among the twelve patients with pathogenic mutations in inherited BMF/MDS genes, genetic testing was consistent with the prior clinical diagnoses of eight patients, including two Fanconi anemia patients subtyped as complementation group A, one of whom demonstrated reversion to wild-type resulting in mosaicism in the peripheral blood. Importantly, four patients carried no specific inherited BMF/MDS diagnosis prior to testing and were found to have pathogenic mutations in RPS10, RTEL1 and RUNX1 (ID 005, 008, 009, 010), suggesting additional diagnostic value to a multiplexed genetic approach in the clinical setting. Detailed clinical information was available for nine of the patients diagnosed with pathogenic mutations, two of whom have or will undergo a sibling or haploidentical hematopoietic stem cell transplantation (009 and 012, respectively) and thus genetic testing informed donor selection. To improve diagnostic accuracy, we are now updating the capture design to include newly discovered inherited BMF/MDS genes and intronic regions to optimize copy number variant detection. We are additionally pursuing CLIA-certified RNA analyses to characterize whether several variants bioinformatically predicted to affect splicing are functionally deleterious. Next-generation sequencing for mutations involved in hereditary marrow failure and MDS may also become increasingly important in the context of precision-medicine in which germline mutations are unexpectedly identified in somatic testing. Disclosures No relevant conflicts of interest to declare.

Late Donor Bone Marrow Failure After Allogeneic Hematopoietic Stem Cell Transplantation

2014 ◽  
Vol 97 (12) ◽  
pp. e75-e77 ◽  
Author(s):  
Mathieu Meunier ◽  
Anne-Claire Manez ◽  
Aliénor Xhaard ◽  
Régis Peffault de Latour ◽  
Flore Sicre de Fontbrune ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Donor Bone Marrow

Immunosuppressive Therapy in Children with Refractory Anemia: Results of Japanese Childhood MDS Study Group Trial (MDS99).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2674-2674
Author(s):  
Daisuke Hasegawa ◽  
Hiroshi Yagasaki ◽  
Yoshitoshi Ohtsuka ◽  
Masami Inoue ◽  
Akira Kikuchi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Disease Progression ◽  
Immunosuppressive Therapy ◽  
Hematopoietic Stem Cell ◽  
Refractory Anemia ◽  
Study Group ◽  
Observation Group ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder and uncommon in childhood. Especially, refractory anemia (RA), which is a subgroup of MDS without an increased number of blasts, is quite rare in this age group. Although hematopoietic stem cell transplantation (HSCT) is thought to be a curative therapy for pediatric MDS, it may cause severe complications and mortality. Several reports have shown encouraging results with immunosuppressive therapy (IST) in adult patients with RA. We report the outcome of 12 children with RA enrolled on a prospective multicenter trial conducted by Japanese childhood MDS study group. In this study, a child who was suspected of having RA required repetitive bone marrow aspiration at 6–8 weeks intervals. If the disease was stable and blood transfusion was not urgent, the patient could be monitored closely without any therapy. If physicians decided to start therapy due to progression of cytopenia, the patient received IST consisting antithymocyte globulin (ATG), cyclosporine (CyA) and methylprednisolone (mPSL). Of the 12 children, 9 received IST (IST group), 2 were followed without treatment (observation group) and one underwent HSCT without IST. Seven children showed hematological response in the IST group, and a response rate was 77.8%. Of note, 1 patient with monosomy 7 showed complete cytogenetic response after IST and remained in remission. One patient became refractory to IST after relapse and underwent bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) 1-antigen mismatch relative, and she is alive without disease on 351 days after HSCT. One patient received BMT from an HLA-matched unrelated donor without IST because he had monosomy 7, but he relapsed and died from disease progression. Neither of 2 patients in the observation group experienced disease progression. There were 8 children who showed chromosomal abnormalities, including monosomy 7 and trisomy 8, 7 of whom received IST and 6 children showed hematological response. No severe adverse events related to IST were reported in this study. Eleven of the 12 patients are alive after a median follow-up of 1,319 days. The probability of survival at 5 years was 88.9%, which was superior to our previous retrospective analysis of children with RA. We conclude that IST for children with RA seems an effective modality and warrants an international clinical trial.

Poor Graft Function in Recipients of T Cell Depleted (TCD) Allogeneic Hematopoietic Stem Cell Transplants (HSCT) Is Mostly Related to Viral Infections and Anti-Viral Therapy.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3147-3147 ◽  
Author(s):  
Roni Tamari ◽  
Sheetal Ramnath ◽  
Deborah Kuk ◽  
Craig S. Sauter ◽  
Doris M Ponce ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Viral Infections ◽  
Graft Function ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Poor Graft Function

Abstract Abstract 3147 Introduction: Poor graft function (PGF) without immune rejection, defined as persistent cytopenias with hypocellular marrow and full donor myeloid chimerism, can be a life-threatening complication after allogeneic HSCT. It is commonly caused by viral infectious, myelosuppressive drugs like antivirals, and graft-vs-host disease (GvHD). Treatment options include supportive therapy with transfusions and growth factors and in severe cases administration of additional hematopoietic stem cells (HSCs) from the same donor without conditioning (stem cell boost). The incidence, natural history, and the indications for stem cell boost therapy are not well defined. Aims: To assess the incidence, etiologies, and indications for stem cell boost for PGF in a homogeneous group of patients with advanced MDS and AML who underwent TCD HSCT from matched or mismatched related or unrelated donors after conditioning with the same myeloablative regimen. Patients and methods: Poor graft function was defined as persistent neutropenia (ANC <1,000 μL and G-CSF administration x3 in 30 days), thrombocytopenia (platelets <50,000 μL or platelets transfusion × 4 in 30 days), and/or hemoglobin <8 g//dL after engraftment with hypocellular BM and full donor myeloid chimerism. Severe PGF was defined as ANC <500 μL, red cell transfusion-dependent anemia with reticulocytopenia of < 20,000 μL, and platelets <20,000 μL. The patient population in which this study was done included 42 patients enrolled between 09/2009 and 05/2012 in a phase 2 trial of palifermin peri-transplant to reduce transplant-related mortality. The median age was 57.5 years (1–65). All patients received the same myeloablative conditioning regimen with busulfan, melphalan, fludarabine, rabbit ATG and palifermin peri-transplant. G-CSF mobilized donor peripheral blood stem cells underwent CD34+ selection and depletion of T cells using CliniMACS immunomagnetic selection columns (Milteny Biotec). Donors were HLA matched (31; 13 related and 18 unrelated) or mismatched unrelated (11). Chimerism was determined in bone marrow as well as neutrophils, B cells, and T cells by short tandem repeat analysis on DNA extracted from bone marrow and peripheral blood cell subsets. Results: Forty-one patients were evaluable for this analysis; 1 patient was not included as he rejected the allograft shortly after engraftment. There were 8 cases of PGF with a cumulative incidence (CI) at 1 year of 18% (13% HLA matched, 33% HLA mismatch). The etiology was infection in 7 cases, and unknown in the 8th case. This patient presented with presumed autoimmune anemia and thrombocytopenia associated with a hypercellular marrow and did not respond to multiple lines of therapies. Her marrow became later hypocellular and met the criteria for PGF. None of the PGF cases in this series was associated with GvHD at the time of diagnosis of PGF. The infectious etiologies included: 6 viral infections and 1bacterial sepsis + myelosuppressive drugs. The most common viral etiology associated with PGF was CMV (50%). The 1-year CI of PGF in CMV seropositive patients was 25% and in CMV seronegative patients was 14%. Of note, HHV6 viremia was detected in patients with PGF. HHV6 is not routinely monitored, however, making it difficult to establish a causative role. All patients had moderate PGF at diagnosis and 3 cases had worsening of cytopenias and met the criteria for severe PGF. To date, 3 PGF patients have died from EBV-PTLD, adenovirus infection or GVHD (developed after CMV treatment with liposomal cidofovir), 3 continue to suffer from PGF and 2 patients are alive with recovered good blood counts after eradication of CMV. Of the 3 patients with persistent PGF, one received a TCD boost with no response, and 2 continued to be treated for CMV viremia. A stem cell boost was indicated if pancytopenia persisted despite eradication of cause of the PGF. In this small series, there were not enough events to evaluate association between PGF and CD34 cell dose, CD3 cell dose or day 100 T-cell chimerism. Conclusions: In this homogenous population of patients with MDS who underwent TCD allogeneic HSCT, the incidence of PGF is about 20%. The most common cause was viral infection with predominance of CMV. Therefore, strategies to prevent CMV reactivation in patients undergoing allogeneic HSCT has the potential to reduce the risk of PGF and avoid the need for infusion of additional stem cells. Disclosures: No relevant conflicts of interest to declare.

Outcome of Pediatric Allogeniec Hematopoietic Stem Cell Transplantation for Nonmalignant Disease: A Single Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4558-4558
Author(s):  
Ibraheem Abosoudah ◽  
Asem Lashin ◽  
Fawwaz Yassin ◽  
Hassan Al trabolsi ◽  
Mohamed Bayoumy
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Failure ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Nonmalignant Disease

Abstract Abstract 4558 Background: The aim of this study was to determine the outcome of pediatric allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for nonmalignant disease in our center. Method: Data were retrospectively collected for all patients (aged 0–18 years) who received allogeneic HSCT between May, 2005 and December, 2011. Outcomes according to the type of transplant, diagnosis, and transplant-related complications are reported. Result: Allo-HSCT was performed in 17 patients, (11 male; 6 female). Bone marrow Failure (7;41%) was the commonest nonmalignant disease followed by B-thalassemia major (4;24%) and others (6;35%). Only HLA-matched family donors were used. Most patients were conditioned with Busulfan/Cyclophosphamide/ATG. GVHD prophylaxis comprised mainly of cyclosporine and methotrexate. The median time to neutrophil engraftment was 20 (9–27) days. Two patients experienced graft failure. Four patients had Grade (I–III) aGVHD and no patient had grade (IV). Four patients (23%) had chronic GVHD. No patient had sinusoidal obstruction syndrome (SOS). Five patients had reactivation of CMV infection, which was treated and resolved in all of them. Only one patient died of sepsis. Overall survival (OS) and event free survival (EFS) were 94%, and 88% respectively. Conclusion: In this cohort of patients, bone marrow failure was the main reason for transplantation. The early results of HSCT were promising and consistent with published international data. Similarly, graft failure remains a concern. Disclosures: No relevant conflicts of interest to declare.

Regulation of Hematopoietic Stem Cells by Interferons and by DNA Methylation: Implications for Bone Marrow Failure

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-20-SCI-20
Author(s):  
Margaret A. Goodell
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Stem Cell Differentiation ◽  
Primary Myelofibrosis ◽  
Differentiation Potential ◽  
Hematopoietic Stem

Bone marrow failure (BMF), the inability to regenerate the differentiated cells of the blood, has a number of genetic and environmental etiologies, such as mutation of telomere-associated protein genes and immune-related aplastic anemia. Recently, mutations in DNA methyltransferase 3A (DNMT3A) have been found to be associated with approximately 15% of cases of primary myelofibrosis (MF), which can be a cause of BMF. The role of DNMT3A more broadly in hematopoiesis, and specifically in BMF, is currently poorly understood. DNMT3A is one of two de novo DNA methylation enzymes important in developmental fate choice. We showed that Dnmt3a is critical for normal murine hematopoiesis, as hematopoietic stem cells (HSCs) from Dnmt3a knockout (KO) mice displayed greatly diminished differentiation potential while their self-renewal ability was markedly increased1, in effect, leading to failure of blood regeneration or BMF. Combined with loss of Dnmt3b, HSCs exhibited a profound differentiation block, mediated in part by an increase of stabilized b-catenin. While we did not initially observe bone marrow pathology or malignancy development in mice transplanted with Dnmt3a KO HSCs, when we aged a large cohort of mice, all mice succumbed to hematologic disease within about 400 days. Roughly one-third of mice developed frank leukemia (acute lymphocytic leukemia or acute myeloid leukemia), one-third developed MDS, and the remainder developed primary myelofibrosis or chronic myelomonocytic leukemia. The pathological characteristics of the mice broadly mirror those of patients, suggesting the Dnmt3a KO mice can serve as a model for human DNMT3A-mutation associated disease. Strikingly, bone marrow of mice with different disease types exhibit distinct DNA methylation features. These will findings and the implications for disease development will be discussed. We are currently investigating the factors that drive different outcomes in the mice, including stressors such as exposure to interferons. We have hypothesized that HSC proliferation accelerates the Dnnmt3a-associated disease phenotypes. We have previously shown that interferons directly impinge on HSCs in the context of infections. Interferons activate HSCs to divide, generating differentiated progeny and cycling HSCs. Repeated interferon stimulation may permanently impair HSC function and bias stem cell output. When combined with loss of Dnmt3a, interferons may promote BMF. We will discuss broadly how external factors such as aging and infection may collaborate with specific genetic determinants to affect long-term hematopoiesis and malignancy development. Reference: Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 2012; 44: 23-31 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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