Familial myelodysplastic syndromes: a review of the literature

Liew, Elena; Owen, Carolyn

doi:10.3324/haematol.2011.043422

Cited by 136 publications

(136 citation statements)

References 58 publications

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“…The risk of malignancies appears even higher in FPD/AML, since over 40% of such patients had myeloid neoplasms. 23 However, as discussed for ETV6-RT, the RUNX1 mutational screening was also generally performed in pedigrees with hematologic malignancies, 24 and it is therefore likely that the incidence of transformation has been overestimated. However, each patient with an inherited thrombocytopenia caused by mutations in ETV6, RUNX1 or ANKRD26 has a relevant risk of hematologic malignancies, and recognizing these patients is important not only to provide effective genetic counseling and appropriate follow-up, but also to give appropriate treatment to patients who develop blood neoplasms and need hematopoietic stem cell transplantation.…”

Section: A B C Dmentioning

confidence: 99%

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

et al. 2016

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Section: A B C Dmentioning

confidence: 99%

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

et al. 2016

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“…The RUNX1 transcription factor (TF) is encoded by one of the most frequently mutated genes in myeloid malignancies, including de novo and secondary acute myeloid leukemia (AML), [1][2][3][4][5] myelodysplasia (MDS), [6][7][8][9][10][11] and chronic myelomonocytic leukemia. 12,13 RUNX1 mutations lead to the expression of no protein, a crippled protein, or a dominant-negative fusion protein (in the case of the (8;21) translocation).…”

Section: Introductionmentioning

confidence: 99%

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Behrens

Triviai

Schwieger

et al. 2016

Blood

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• Runx1 is a key determinant of megakaryocyte cell-fate decisions in multipotent progenitors.• Runx1 downregulates celladhesion factors that promote residency of stem cells and megakaryocytes in their bone marrow niche.Disrupting mutations of the RUNX1 gene are found in 10% of patients with myelodysplasia (MDS) and 30% of patients with acute myeloid leukemia (AML). Previous studies have revealed an increase in hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells in conditional Runx1-knockout (KO) mice, but the molecular mechanism is unresolved. We investigated the myeloid progenitor (MP) compartment in KO mice, arguing that disruptions at the HSC/MPP level may be amplified in downstream cells. We demonstrate that the MP compartment is increased by more than fivefold in Runx1 KO mice, with a prominent skewing toward megakaryocyte (Meg) progenitors. Runx1-deficient granulocyte-macrophage progenitors are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. An HSC/MPP subpopulation expressing Meg markers was also increased in Runx1-deficient mice. Rescue experiments coupled with transcriptome analysis and Runx1 DNA-binding assays demonstrated that granulocytic/monocytic (G/M) commitment is marked by Runx1 suppression of genes encoding adherence and motility proteins (Tek, Jam3, Plxnc1, Pcdh7, and Selp) that support HSC-Meg interactions with the BM niche. In vitro assays confirmed that enforced Tek expression in HSCs/MPPs increases Meg output. Interestingly, besides this key repressor function of Runx1 to control lineage decisions and cell numbers in progenitors, our study also revealed a critical activating function in erythroblast differentiation, in addition to its known importance in Meg and G/M maturation. Thus both repressor and activator functions of Runx1 at multiple hematopoietic stages and lineages likely contribute to the tumor suppressor activity in MDS and AML. (Blood. 2016;127(26):3369-3381)

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“…Az első jól dokumentált familiáris hematológiai kórkép, napjainkig több mint 30 családfát tártak fel [1,19]. A kórkép jellegzetessége a változó fokú vérzészavar, amely rejtve is maradhat, de meg is nyilvánulhat thrombocytaszám-eltérésben és enyhe-középsúlyos vérzékenység formájában is [20]. A vérlemezke-funkciózavarból kifejlődő MDS/ AML rizikója mintegy 40% az egész élethossz alatt [21].…”

Section: Familiáris Vérlemezke-funkciózavar Talaján Kialakuló Mds/amlunclassified

Familiáris myelodysplasiás szindróma és akut myeloid leukaemia klinikai és genetikai háttere

et al. 2016

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A myelodysplasiás szindróma és az akut myeloid leukaemia döntően sporadikus megbetegedések, azonban a fiatalkorban előforduló, illetve a családi halmozódást mutató esetekről egyre gyakrabban derül ki, hogy valójában örökletes kórképek, amelyek hátterében a myeloid vérképzést szabályozó faktorok autoszomális domináns mutációi állnak. Ezen örökletes mutációk jellegzetes szindrómákat hoznak létre, amelyek fokozott kockázattal járnak myelodysplasia és akut leukaemia kialakulására (prediszpozíciós szindrómák). Jelenleg négy ilyen szindróma ismert: (1) a CEBPA-, valamint a (2) GATA2-mutációt hordozó familiáris myelodysplasia/akut leukaemia, (3) a familiáris vérlemezke-funkciózavar talaján kialakuló myelodysplasia a RUNX1 gén mutációjával és (4) a telomerázbiológiát érintő kórképek, amelyek a TERT vagy TERC gének mutációival jellemezhetők. A közelmúltban derült ki, hogy az ANKRD26, ETV6, SRP72 és DDX41 gének mutációi szintén szerepet játszhatnak familiáris myeloid kórképek kialakításában. Jelen ösz-szefoglaló közlemény célja e különleges betegségcsoportra való figyelemfelhívás, valamint e kórképek genetikai és klinikai hátterének ismertetése. Orv. Hetil., 2016, 157(8), 283-289. Kulcsszavak: germline mutáció, familiáris leukaemia, CEBPA, GATA2, RUNX1, MDS Clinical and genetic background of familial myelodysplasia and acute myeloid leukemiaMyelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia.

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Familial myelodysplastic syndromes: a review of the literature

Cited by 136 publications

References 58 publications

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

Clinical and pathogenic features of ETV6 -related thrombocytopenia with predisposition to acute lymphoblastic leukemia

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Familiáris myelodysplasiás szindróma és akut myeloid leukaemia klinikai és genetikai háttere

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