Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failure

Heidemann, Stephanie C.; Bursic, Brian; Zandi, Sasan; Li, Hongbing; Abelson, Sagi; Klaassen, Robert J.; Abish, Sharon; Rayar, Meera; Breakey, Vicky R.; Moshiri, Houtan; Dhanraj, Santhosh; Borja, Richard de; Dick, John E.; Dror, Yigal

doi:10.1172/jci.insight.131018

Cited by 8 publications

(4 citation statements)

References 79 publications

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“…Another NGS study of 7 patients with FA (includ ing 1 with AML) also con firmed fre quent CH from a young age, vir tu ally observed in all patients tested, regard less of the pres ence of periph eral blood cytopenia or leu ke mia. 29 One AML sam ple in that study car ried mul ti ple MDS/AML muta tions, includ ing TP53. Although a clear pat tern of clonal evo lu tion can not be deter mined from these stud ies due to small sam ple sizes, a rel a tive lack of DNMT3A, TET2, and SF3B1 was observed in both stud ies, sug gesting the dif fer ent somatic muta tional spec trum in FA.…”

Section: Fanconi Ane Miamentioning

confidence: 96%

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

2021

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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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Section: Fanconi Ane Miamentioning

confidence: 96%

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

2021

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“…21 Aberrations in RUNX1 were found in patients with FA as well as rare mutations in other genes. 22,23 Of our four patients with FA, two had somatic mutations, including in SF3B1, PPM1D and RUNX1. SAMD9 and SAMD9L are paralogue genes in which germline mutations cause predisposition to the development of MDS/AML as well as extra haematopoietic abnormalities.…”

Section: Somatic Mutations In Patients With Ibmfs and Other Mds/aml Predisposing Syndromesmentioning

confidence: 98%

Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias

et al. 2020

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Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS-predisposition syndromes, prior to the development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next-generation-sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty-five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS-predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty-eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS-predisposition syndromes may reveal their unique spectrum of acquired mutations.

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“…The reason is that most FA patients are diagnosed when they have substantial cytopenia and their hematopoietic stem cells are depleted. 6 …”

mentioning

confidence: 99%

“…The reason is that most FA patients are diagnosed when they have substantial cytopenia and their hematopoietic stem cells are depleted. 6 Several gene therapy trials have been conducted in FA and various others are currently being conducted in Europe and the USA. Preliminary data showed that FANCA gene therapy without conditioning therapy is safe in FA and corrected cells are engrafted and manifest a proliferative advantage.…”

mentioning

confidence: 99%