GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis

Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of the EVI1 gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the EVI1 gene reciprocally deprives this enhancer of 1 of the 2 GATA2 alleles, resulting in a loss-of-function genetic reduction in GATA2 abundance. Because GATA2 haploinsufficiency is strongly associated with MDS and AML, we asked whether EVI1 misexpression and GATA2 haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven EVI1 misexpression, but in this case, it was coupled to a Gata2 heterozygous germ line deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemic transformation, resulting in early onset of leukemia. The 3q21q26 mice suffered from leukemia in which B220+ cells and/or Gr1+ leukemic cells occupied their bone marrows. We found that the B220+Gr1–c-Kit+ population contained leukemia-initiating cells and supplied Gr1+ leukemia cells in the 3q21q26 leukemia. When Gata2 expression levels in the B220+Gr1–c-Kit+ cells were decreased as a result of Gata2 heterozygous deletion or spontaneous phenomenon, myeloid differentiation of the B220+Gr1–c-Kit+ cells was suppressed, and the cells acquired induced proliferation as well as B-lymphoid–primed characteristics. C...
Source: Blood - Category: Hematology Authors: Tags: Myeloid Neoplasia Source Type: research

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Publication date: Available online 9 November 2017Source: Seminars in Cancer BiologyAuthor(s): Christian Flotho, Sebastian Sommer, Michael LübbertAbstractMyelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular resp...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Publication date: July 2018Source: Journal of Geriatric Oncology, Volume 9, Issue 4Author(s): Marlise R. Luskin, Gregory A. AbelAbstractThe myelodysplastic syndromes (MDS) are a varied group of hematologic neoplasms that lead to bone marrow failure, and also carry a risk of progression to acute myeloid leukemia. Patients with MDS suffer significant impairments to both their quality of life and survival. Age is the dominant risk factor for the development of MDS, with a median age at diagnosis over 70 years. Consequently, patients with MDS frequently have concurrent comorbidities and/or frailty which may be coincident ...
Source: Journal of Geriatric Oncology - Category: Cancer & Oncology Source Type: research
We report a case of myelodysplastic syndrome progressing to AML with calreticulin driver mutation in an adult male with TAR syndrome who was successfully treated with hematopoietic allogeneic stem cell transplantation.
Source: Hematology Oncology and Stem Cell Therapy - Category: Cancer & Oncology Source Type: research
Publication date: Available online 9 November 2017Source: Seminars in Cancer BiologyAuthor(s): Christian Flotho, Sebastian Sommer, Michael LübbertAbstractMyelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular resp...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research
Publication date: July 2018Source: Journal of Geriatric Oncology, Volume 9, Issue 4Author(s): Marlise R. Luskin, Gregory A. AbelAbstractThe myelodysplastic syndromes (MDS) are a varied group of hematologic neoplasms that lead to bone marrow failure, and also carry a risk of progression to acute myeloid leukemia. Patients with MDS suffer significant impairments to both their quality of life and survival. Age is the dominant risk factor for the development of MDS, with a median age at diagnosis over 70 years. Consequently, patients with MDS frequently have concurrent comorbidities and/or frailty which may be coincident ...
Source: Journal of Geriatric Oncology - Category: Cancer & Oncology Source Type: research
We report a case of myelodysplastic syndrome progressing to AML with calreticulin driver mutation in an adult male with TAR syndrome who was successfully treated with hematopoietic allogeneic stem cell transplantation.
Source: Hematology Oncology and Stem Cell Therapy - Category: Cancer & Oncology Source Type: research
Hematopoietic allogeneic stem cell transplantation (HSCT) is an accepted and potentially curative treatment for a variety of hematological diseases, immunodeficiencies and metabolic disorders1, with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) to date representing more than half of the indications in adult patients2. An HLA-matched related donor (MRD) is available for about 25% of patients, while the probability of finding a fully HLA-matched unrelated donor (MUD) varies on average between 60 and 90%3,4.
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
Bone marrow failure and related syndromes are rare disorders characterized by ineffective bone marrow hematopoiesis and peripheral cytopenias. Although many are associated with characteristic clinical features, recent advances have shown a more complicated picture with a spectrum of broad and overlapping phenotypes and imperfect genotype – phenotype correlations. Distinguishing acquired from inherited forms of marrow failure can be challenging, but is of crucial importance given differences in the risk of disease progression to myelodysplastic syndrome, acute myeloid leukemia, and other malignancies, as well as the p...
Source: Seminars in Hematology - Category: Hematology Authors: Tags: Review Source Type: research
Allogeneic stem cell transplantation (alloSCT) is a potentially curative therapeutic option for patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Disease relapse occurs in 35-45% of patients following alloSCT, and is the most frequent cause of treatment failure and mortality [1-4]. Moreover, relapse after alloSCT is associated with poor prognosis despite salvage chemotherapy, donor lymphocyte infusions, and/or second transplants [4].
Source: Biology of Blood and Marrow Transplantation - Category: Hematology Authors: Source Type: research
AbstractRecently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients withGA...
Source: Annals of Hematology - Category: Hematology Source Type: research
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