scholarly journals Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells

Leukemia ◽  
2021 ◽  
Author(s):  
Melvin E. Thomas ◽  
Sherif Abdelhamed ◽  
Ryan Hiltenbrand ◽  
Jason R. Schwartz ◽  
Sadie Miki Sakurada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Transcriptional Profiling ◽  
Hematopoietic Cells ◽  
Protein Translation ◽  
Germline Mutations ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Cellular Environment ◽  
Primary Mouse

AbstractPediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.

scholarly journals Role of Genetic Evolution and Germline Mutations in SAMD9 and SAMD9L Genes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-33-SCI-33
Author(s):  
Jason R Schwartz ◽  
Marcin W. Wlodarski ◽  
Jeffery M. Klco
Keyword(s):  
Bone Marrow ◽  
Germline Mutation ◽  
Bone Marrow Failure ◽  
Hematopoietic Cells ◽  
Germline Mutations ◽  
Chromosome 7 ◽  
Chromosome Loss ◽  
Wild Type ◽  
In Vivo Models ◽  
Monosomy 7

Acquired deletions on chromosome 7 (monosomy 7/del7q) are common in myeloid neoplasms, especially pediatric MDS and AML. Although these tumors have historically been reported to occur within families, suggesting a genetic predisposition, the genetic lesion(s) that initiate these diseases has remained elusive until the last few years. Following a series of publications in which germline mutations in SAMD9 and SAMD9L were reported in a MIRAGE syndrome and Ataxia Pancytopenia syndrome, respectively, our group and others described similar heterozygous missense germline mutations in pediatric MDS, especially non-syndromic familial MDS with monosomy 7. Mutations in SAMD9 and SAMD9L have now also been reported in transient monosomy 7, inherited bone marrow failure and AML. Collectively, it is estimated that germline mutations in these genes are present in nearly 20% of children with MDS, with a strong enrichment in those with monosomy 7. Surprisingly, SAMD9 and SAMD9L are paralogous genes adjacently located on human chromosome 7 at band 7q21, and the monosomy 7 clone that expands in children universally lacks the pathologic germline variant. Expression of the mutant proteins in cells results in profound growth suppression, suggesting that there is strong selective pressure for hematopoietic cells to not express the mutant alleles. In addition to chromosome loss, additional methods that suppress expression of the pathologic allele have been described. These include copy neutral loss of heterozygosity (CN-LOH) with duplication of the wild-type allele or the somatic acquisition of additional mutations in cis with the germline mutation that counteract the growth suppressive effect of the germline mutation. The clinical phenotype is largely dictated by the revertant mutation in the dominant hematopoietic clone within the patient's bone marrow. Those with an expansion of a CN-LOH clone are more commonly asymptomatic, in contrast to those patients with a dominant monosomy 7 clone. Progression to higher grade MDS or AML is associated with the acquisition of additional somatic mutations including mutations in SETBP1, KRAS and RUNX1. The recognition of these germline mutations has had an immediate impact on the clinical management of children with MDS, including their family members, and ongoing clinical work in the pediatric MDS community is aimed at establishing guidelines for the pathologic diagnosis, clinical monitoring and treatment for these patients. In addition to these ongoing clinical pursuits, there is significant research interest in these genes, the function of their proteins in hematopoietic cells and how the germline mutations alter the function of the wild-type protein. The SAMD9 and SAMD9L proteins are largely uncharacterized and have been shown to be important in endocytosis, growth factor signaling and to have antiviral properties. Intriguingly, SAMD9 and SAMD9L are both induced by inflammatory signals, including interferons, suggesting a link between inflammatory stress and the disease phenotype. Ongoing studies are aimed at developing models, including in vitro and in vivo models, to understand the mechanisms by which these germline mutations can ultimately lead to the development of pediatric MDS and related disorders. Disclosures No relevant conflicts of interest to declare.

Modeling Bone Marrow Failure and MDS in Shwachman Diamond Syndrome Using Induced Pluripotent Stem Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1496-1496 ◽  
Author(s):  
Melisa Ruiz-Gutierrez ◽  
Ozge Vargel Bolukbasi ◽  
Linda Vo ◽  
Ryohichi Sugimura ◽  
Marilyn Sanchez Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Chromosome 7 ◽  
Stem Cell Markers ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Myelodysplastic syndrome (MDS) caused by monosomy 7 or del(7q) is a frequent clonal abnormality that arises in the context of inherited bone marrow failure syndromes, such as Shwachman Diamond Syndrome (SDS). Monosomy 7/del(7q) also develops in a subset of patients with acquired aplastic anemia or de novo MDS in the general population. Monosomy 7/del(7q) is associated with high grade MDS and a high risk of malignant transformation, most frequently to acute myelogenous leukemia (AML). Bone marrow failure and clonal evolution to MDS and AML remain major causes of morbidity and mortality for individuals with SDS. Currently, the only curative therapy for these hematological complications is a hematopoietic stem cell transplant. Prognosis is extremely poor once SDS patients develop leukemia. The basis for this propensity to develop monosomy 7 clones remains unclear. The longterm aim of this study is to understand the molecular mechanisms underlying leukemia predisposition and develop more effective treatments. Whether monosomy 7/del(7q) functions as a driver of MDS, or is merely an associated marker of clonal progression in bone marrow failure remains a critical question. The lack of synteny between murine versus human chromosome 7 has posed a major barrier to the development of mouse models of monosomy 7/del(7q). To study the biological and molecular consequences of monosomy 7/del(7q) in SDS, induced pluripotent stem cells (iPSCs) were generated from bone marrow mononuclear cells of two patients with SDS. Each patient harbored homozygous c.258+2 T>C mutations in the canonical splice donor site of intron 2 in the SBDS gene. The SDS-iPSCs retained the pathogenic homozygous IVS2+2 T>C SBDS mutations, expressed stem cell markers, formed teratomas, and expressed reduced levels of SBDS protein similar to levels noted in the primary patient samples. Proliferation of 4 distinct SDS-iPSC clones derived from two different patients was reduced relative to wild type controls without an increase in cell death. SDS-iPSC formed smaller embryoid bodies with reduced production of CD34+ hematopoietic stem/progenitor cells. Hematopoietic differentiation from CD34+ to CD45+ cells was also impaired. Preliminary data suggest that SDS-iPSCs retain the capacity to give rise to hematopoietic stem/progenitor cells and early myeloid progenitor cells in vitro. These populations were also observed in primary SDS patient-derived bone marrow samples. Because the number of CD34+ cells derived from SDS-iPSCs are limiting, a previously reported 5 transcrition factor re-specification system was used to expand multilineage hematopietic progenitors for further characterization. SDS iPSCs were able to differentiate into an expandable CD34+ population in vitro. Further studies to characterize the hematopoietic impairment in SDS iPSC and primary marrow samples are ongoing. To model del(7q) in SDS iPSCs, a deletion of the MDS-associated long arm of chromosome 7 was genomically engineered using a previously published modified Cre-Lox approach. The deletion of 7q at locus (11.2) was confirmed by karyotyping and by qPCR across chromosome 7. The SDS (del7q) iPSCs retained the SBDS pathogenic mutations, expressed stem cell markers, and formed teratomas. Proliferation of the SDS del(7q) iPSC was markedly impaired compared to isogenic SDS iPSCs. No increase in cell death was observed in the SDS del7q iPSCs. Studies are in progress to determine the effects of del7q on hematopoiesis. Investigation is ongoing to determine the molecular consequences of deleting 7q. These isogenic SDS+/- del(7q) iPS models provide a platform to study the role of 7q loss in clonal evolution from bone marrow failure and to screen for novel therapeutic compounds or pathways to treat bone marrow failure and MDS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acquired Aplastic Anemia: New Genetics, New Genomics

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-21-SCI-21
Author(s):  
Neal S. Young ◽  
Bogdan Dumitriu ◽  
Seishi Ogawa
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Somatic Mutations ◽  
Bone Marrow Failure ◽  
Single Agent ◽  
Laboratory Data ◽  
Gene Sequencing ◽  
Chromosome Loss ◽  
Hematopoietic Stem ◽  
Monosomy 7

Clinical and laboratory data have established that aplastic anemia is an immune-mediated disease in which T lymphocytes destroy hematopoietic stem and progenitor cells. Immunosuppressive therapies are effective in the majority of patients. Addition of the thrombopoietin mimetic eltrombopag increases the overall and complete response rates to anti-thymocyte globulin and as a single agent can rescue patients refractory to immunosuppressive therapy (IST). Multi-lineage robust blood count improvements with increased marrow cellularity suggest activity of eltrombopag on the hematopoietic stem cell. Recently, genetic factors have been identified that increase the risk of bone marrow failure: adults may present in the clinic with late manifestations of a pediatric syndrome (dyskeratosis congenita), but more typically there are no physical anomalies, often no family history, and earlier blood counts may be normal. In the telomeropathies, which in later life are almost always due to mutations in TERT (which encodes the telomerase) or TERC (which encodes the RNA template), there may be personal or familial multi-organ involvement, especially of liver and lung; early hair greying is a useful clinical clue. Detection of extremely short telomeres of leukocytes, accompanied by gene sequencing, is used to establish the diagnosis. In the syndrome defined by GATA2 mutations, there may be a history of unusual or persistent mycobacterial and viral infections, and monocytopenia preceding pancytopenia. Diagnosis requires sophisticated interpretation of gene sequencing. Large genomic data sets are now available acquired (somatic) mutations in aplastic anemia. For almost 300 NIH aplastic anemia patients treated with IST, candidate gene sequencing of myeloid cells obtained six months after treatment revealed somatic mutations in about one-third of cases. PIGA was most frequently abnormal, followed by BCOR1, DNMT3A, and ASXL1. Initial variant allele frequency was usually low. Mutations in a subset of genes predicted poor survival and progression to myelodysplastic syndrome and acute myeloid leukemia, while mutations in BCOR and PIGA correlated favorably with outcomes. When we also examined a subset of patients at the time of progression to monosomy 7 with pancytopenia and/or incipient leukemia by whole exome sequencing.DNMT3A and ASXL1 were implicated in only two cases, RUNX1 in another, and there were no novel recurring mutations. Telomere attrition was markedly accelerated in these monosomy 7 cases. A good model of evolution from bone marrow failure to myeloid malignancy centers on haploinsufficiency of specific genes, by mutations or chromosome loss, both of which would be favored in a stressed, regenerative environment. The failed marrow environment may select for defective cells, as, for example, in differentiation capability. Malignant evolution should be predictable in the clinic and amenable to therapeutic intervention. Disclosures Off Label Use: Eltrombopag in bone marrow failure syndromes, research protocols.

Cytokinesis Failure In Fanconi Anemia Pathway Deficient Hematopoietic Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 878-878
Author(s):  
Kalindi Parmar ◽  
Patrizia Vinciguerra ◽  
Susana Godinho ◽  
Abigail Hamilton ◽  
David Pellman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Hematopoietic Cells ◽  
Fibroblast Cells ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
Binucleated Cells ◽  
Hoechst Staining

Abstract Abstract 878 Fanconi Anemia (FA) is a human genomic instability disorder characterized by progressive bone marrow failure, congenital abnormalities and high predisposition to cancer. Bone marrow failure in FA children is attributed partly to the excessive apoptosis and subsequent failure of the hematopoietic stem cell compartment. Understanding the mechanisms of bone marrow failure may allow better diagnosis and treatment for FA and other aplastic anemia patients. There are fourteen known Fanconi Anemia genes (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O). The FA pathway, regulated by these FA gene products, mediates DNA repair and promotes normal cellular resistance to DNA crosslinking agents. Recent studies suggest that besides maintaining genomic stability, the FA pathway may also play a role in mitosis since FANCD2 and FANCI, the two key FA proteins, are localized to the extremities of ultra-fine DNA bridges (UFBs) linking sister chromatids during cell division (Chan et al, Nat Cell Biol, 11:753-760, 2009; Naim and Rosselli, Nat Cell Biol, 11:761-768, 2009). Whether FA proteins play a direct role in cell division is still unclear. To dissect the mechanisms of bone marrow failure in FA, we have investigated the requirement of FA pathway during mitosis. Initially, we investigated the number of DNA bridges occurring during mitosis in FA-deficient and proficient cells by immunofluorescence and Hoechst staining. FA-deficient patient cell lines (FANCG-deficient and FANCD1/BRCA2-deficient cells) as well as Hela cells with shRNA-mediated knockdown of the FA pathway, displayed an increase in UFBs compared to the FA proficient cells during mitosis. The UFBs were coated by BLM (the RecQ helicase mutated in Bloom syndrome) in early mitosis. In contrast, the FA protein, FANCM, was recruited to the bridges at a later stage. Since the DNA bridges occluding the cleavage furrow potentially induce cytokinesis failure, we assessed FA-deficient cells for multinucleation. The increased number of DNA bridges correlated with a higher rate of binucleated cells in FA deficient Hela cell lines and FA patient-derived fibroblast cells. Moreover, an increase in binucleated cells was also detectable in FA-deficient primary murine bone marrow hematopoietic stem cells (Fancd2-/- cells and Fancg-/- cells) compared to the wild-type cells undergoing proliferation and in FA patient-derived bone marrow stroma cells compared to the stroma cells from normal human bone marrow. Interestingly, the increase in binucleated cells in FA-deficient murine hematopoietic stem cells correlated with the increase in apoptotic cells. Binuclearity, scored by immunostaining for microtubules and Hoechst staining for DNA, was the result of cytokinesis failure as observed by live cell imaging. Therefore, we investigated whether the FA-deficient cells are sensitive to the cytokinesis inhibitors. FA-deficient murine bone marrow lineage negative cells (Fancd2-/- cells) or FA human fibroblast cells were exposed to VX-680 (an inhibitor of Aurora kinases regulating cytokinesis) in culture for 72 hrs and cell survival was assessed. VX-680 caused increased toxicity (reduced cell viability and increased apoptosis) on FA-deficient cells in comparison to the wild-type cells. Enhanced inhibition of clonogenic growth of murine FA-deficient bone marrow cells (Fancd2-/- cells) compared to the wild-type cells was also observed by exposure to VX-680. These data indicated that FA pathway-deficient hematopoietic cells are hypersensitive to cytokinesis inhibitors. Collectively, our results underscore the importance of the FA pathway in mitosis and suggest that the cytokinesis failure observed in FA deficient hematopoietic cells could contribute to bone marrow failure in Fanconi anemia patients. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
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.

Outcome and Clinical Characteristics of Clonal and Malignant Myeloid Transformation in Inherited Bone Marrow Failure Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1266-1266
Author(s):  
Michaela Cada ◽  
Catherine I. Segbefia ◽  
Robert J. Klaassen ◽  
Conrad V Fernandez ◽  
Rochelle Yanofsky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Characteristics ◽  
Bone Marrow Failure ◽  
Cytogenetic Abnormality ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Cytogenetic Abnormalities ◽  
Bone Marrow Failure Syndromes ◽  
Overall Mortality

Abstract Abstract 1266 Introduction: Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic disorders with a risk of clonal and malignant myeloid transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The clinical characteristics and outcome of IBMFS-related clonal and malignant myeloid transformation are unclear, particularly in cases of early transformation such as isolated clonal marrow cytogenetic abnormalities. Objectives: The aims of this study were to determine the risk and clinical outcome of IBMFS-related clonal and malignant myeloid transformation using data from the Canadian Inherited Marrow Failure Registry (CIMFR). Methods: The CIMFR is a multicenter collaborative study which is intended to enroll all patients with IBMFSs in Canada. The registry was approved by the Institutional Ethics Board of all the participating institutions, and includes 15 of 16 pediatric tertiary care centers across all provinces in Canada. We estimate that these centers care for >95% of the eligible pediatric IBMFS population in Canada. The CIMFR is population-based as >90% of the patients in this study are from centers who enrolled >80% of the patients in their institutions. Clonal and malignant myeloid transformation was defined as having either clonal marrow cytogenetic abnormalities or prominent bi-lineage morphologic dysplasia or increased percentage of marrow blasts (≥5%) or a combination of the above. Results: Among 327 IBMFS patients enrolled on the CIMFR, 45 (13.8%) developed clonal and malignant myeloid transformation. In these 45 patients, the three most common IBMFS diagnoses were Fanconi anemia (31.1%), Shwachman-Diamond syndrome (20.0%) and unclassifiable IBMFSs (28.9%). Clonal marrow cytogenetic abnormalities were identified in 38/45 (84.4%) patients, while 5/45 (11.1%) patients had constitutional cytogenetic changes, 1/45 patients had AML with no cytogenetic abnormalities and 1/45 patients had no cytogenetic abnormalities. Two out of the 5 patients with constitutional cytogenetic abnormalities developed a clonal marrow cytogenetic abnormality later in their disease course. The most common clonal marrow cytogenetic abnormality was monosomy 7, which was found in 14/38 (36.8%) patients. Cytology in the majority of patients 20/45 (44.4%) was consistent with refractory cytopenia. Eight out of the 45 patients developed AML and 2 of these patients had monosomy 7. Twenty-two out of 45 (48.9%) patients with clonal and malignant myeloid transformation underwent hematopoietic stem cell transplantation due to severe cytopenia, excess blasts or leukemia. Fourteen out of the 22 (63.6%) transplanted patients are alive at last follow-up. Out of 8 patients who had AML, 3 received transplant and are alive at last follow-up. The 5 remaining AML patients died; 3 while awaiting transplant, 1 did not achieve remission and 1 refused transplant. Overall mortality in the group of patients with clonal and malignant myeloid transformation was 15/45 (33.3%) at a median follow-up of 10 months from diagnosis with clonal and malignant myeloid transformation. Overall mortality in those 282 patients on CIMFR without clonal and malignant myeloid transformation is 6.4%. Conclusion: Despite short-term follow-up of patients on the CIMFR, a relatively high prevalence of clonal and malignant myeloid transformation was found. Clonal marrow cytogenetic abnormalities are associated with a high risk of progression into advanced MDS or AML and death. Disclosures: No relevant conflicts of interest to declare.

Paroxysmal Nocturnal Hemoglobinuria (PNH) In Pediatric Patients: Review of a Single Center Series

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2231-2231
Author(s):  
Kevin J. Curran ◽  
Nancy A. Kernan ◽  
Susan E. Prockop ◽  
Andromachi Scaradavou ◽  
Trudy N. Small ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stable Disease ◽  
Pediatric Patients ◽  
Bone Marrow Failure ◽  
Adult Population ◽  
Single Center ◽  
Intravascular Hemolysis ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
5Q Deletion

Abstract Abstract 2231 Background: PNH arises from a genetic mutation of hematopoietic stem cells which leads to the acquired nonmalignant clonal expansion of cells lacking glycosyl phosphatidylinositol-anchored proteins (GPI-APs). Lack of GPI-APs translates into PNH's most significant clinical features: bone marrow failure, intravascular hemolysis and thrombosis. PNH rarely occurs in children and has been reported to have a distinct clinical presentation compared to the adult population. Results: We provide a clinical description of 11 consecutive pediatric patients (pts) aged 11–17 years (median age 13.9 years) diagnosed with PNH since 1993 at a single institution. Bone marrow failure was the presenting clinical finding in 10 pts, including aplastic anemia (AA) (N = 9), hypoplastic myelodysplastic syndrome (MDS) (N = 1), and isolated red cell anemia (N = 1). This rate of bone marrow failure at presentation is higher than the reported rate of 24–33% seen in adult pts. Immunosuppressive therapy was the initial treatment for 8 patients with aplastic anemia and this included: antithymocyte globulin (N = 8), Cyclosporine (N = 8) and prednisone (N = 6). Partial response to immunotherapy was seen in all pts. Five pts had evidence of myelodysplastic features, including one at diagnosis. These included dysplasia with monosomy 7 for 2 pts, 5q deletion for one pt, and dysplasia with normal cytogenetics for 2 pts. The monosomy 7 abnormality was transient and resolved spontaneously for the 2 pts, while the pt with 5q deletion proceeded to transplantation. None of these pts developed excessive blasts or leukemic transformation. Thrombosis occurred in six pts with four of the pts experiencing several sites and episodes of thrombosis. Diagnosis of thrombosis occurred at presentation in one patient. Thrombosis in the remaining five pts first occurred 5–88 months from diagnosis (mean 58.8 months). This rate of thrombosis (55%) is similar to the reported rate of thrombosis in adult pts (40%) but is higher than recent reports of pediatric PNH in the literature. Treatment of thrombosis included anticoagulation and thrombolysis when appropriate. Intermittent episodes of intravascular hemolysis occurred in all 11 pts. Gross hemoglobinuria occurred in only one patient at initial presentation. This rate of gross hemoglobinuria at presentation is similar to other series of pediatric PNH, but much lower than the reported rate of 33–50% in adult pts. Of the 11 pts, 4 underwent hematopoietic stem cell transplant (HSCT) of whom 2 pts are alive and disease free. Eculizumab, a monoclonal antibody directed against the complement protein C5 was initiated in 3 pts of whom 2 pts currently have stable disease; the third non-compliant patient developed progression of thrombotic disease but has since restarted eculizumab therapy. Two pts died following complications related to thrombosis and two patients are transfusion independent with stable disease. Conclusions: This series represents a large single center cohort of pediatric pts diagnosed with PNH. This report highlights the high rate of bone marrow failure in pediatric pts with PNH. This differs from the adult population, and emphasizes the need for PNH testing in all children with AA or MDS, as well as children with unexplained Coombs-negative hemolysis or thrombosis. Both the high prevalence of hemolysis and high risk of thrombosis should warrant early treatment with eculizumab for pediatric pts with PNH. HSCT remains the only curative option for pediatric pts with PNH but its risk must be considered relative to the patient's disease severity, compliance and response to long-term treatment with anticoagulant and/or anticomplement therapy. Disclosures: No relevant conflicts of interest to declare.

Necroptosis of a Small Subset of Hematopoietic Progenitors Induces Autoimmune Bone Marrow Failure

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4784-4784
Author(s):  
Junping Xin ◽  
Ni Allen ◽  
Rafael Gutierrez ◽  
Haiyan Chen ◽  
Jing Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Bone Marrow Failure ◽  
Disease Onset ◽  
Hematopoietic Cells ◽  
Clinical Manifestations ◽  
Small Subset ◽  
Autoimmune Reaction ◽  
Hematopoietic Stem ◽  
Tnf Α

Abstract Acquired aplastic anemia (AAA) is an autoimmune-mediated bone marrow failure (BMF) syndrome. Cryptic clonal genetic lesions were commonly detected in a small subset of hematopoietic stem/progenitor cells (HSPCs) in most patients' BM samples. The mechanism by which the autoimmune reaction is initiated is unknown. Whether and how these cryptic clonal genetic lesions might cause autoimmune BMF have not yet been determined. We found that mice with spontaneous deletion of the TGFβ-activated kinase-1 (Tak1) gene in a small subset of HSPCs (1-3%) developed BMF which resembled the clinical manifestations of AAA patients. BMF in such mice could be reversed by depletion of CD4+ T lymphocytes or treatment with IFN-γ, suggesting a Th1 cell-mediated autoimmune mechanism. Interestingly, the disease onset and progression of BMF in such mice were significantly accelerated by inactivation of TNF-α signaling, indicating that TNF-α might restrict the progression of autoimmune BMF. Furthermore, we determined that the necroptosis of a small subset of hematopoietic cells is the cause of autoimmune BMF because such BMF can be completely prevented by deletion of Rip3, a key necroptotic mediator. Our study suggested that the necroptosis of a small subset of hematopoietic cells induces autoimmune BMF, and that elevated TNF-α restricts the progression of such autoimmune BMF. We believe that, in addition to inhibiting T-cell-mediated autoimmune reactions to induce disease remission, repression of the necroptosis of mutant HSPCs might be necessary to prevent disease relapse and progression of autoimmune BM failure. Disclosures Stiff: Gilead: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Fate Therapeutics: Research Funding; Plasmacyclics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding.

scholarly journals How I treat myelodysplastic syndromes of childhood

Blood ◽  
2018 ◽  
Vol 131 (13) ◽  
pp. 1406-1414 ◽  
Author(s):  
Franco Locatelli ◽  
Brigitte Strahm
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Germ Line ◽  
Bone Marrow Failure ◽  
Hematologic Malignancies ◽  
Suppressive Therapy ◽  
Severe Neutropenia ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L. Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse.

scholarly journals Mechanisms of somatic transformation in inherited bone marrow failure syndromes

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 390-398
Author(s):  
Haruna Batzorig Choijilsuren ◽  
Yeji Park ◽  
Moonjung Jung
Keyword(s):  
Bone Marrow ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Germline Mutations ◽  
Partial Recovery ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
Somatic Transformation ◽  
Genomic Studies

Abstract Inherited bone marrow failure syndromes (IBMFS) cause hematopoietic stem progenitor cell (HSPC) failure due to germline mutations. Germline mutations influence the number and fitness of HSPC by various mechanisms, for example, abnormal ribosome biogenesis in Shwachman-Diamond syndrome and Diamond-Blackfan anemia, unresolved DNA cross-links in Fanconi anemia, neutrophil maturation arrest in severe congenital neutropenia, and telomere shortening in short telomere syndrome. To compensate for HSPC attrition, HSPCs are under increased replication stress to meet the need for mature blood cells. Somatic alterations that provide full or partial recovery of functional deficit implicated in IBMFS can confer a growth advantage. This review discusses results of recent genomic studies and illustrates our new understanding of mechanisms of clonal evolution in IBMFS.

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