The hypomorphic Gata1low mutation alters the proliferation/differentiation potential of the common megakaryocytic-erythroid progenitor

Abstract

Recent evidence suggests that mutations in the IntroductionAmong the GATA family of transcription factors, 1 Gata1 exerts a specific role in the control of erythroid, 2 megakaryocytic, 3,4 eosinophil, 5 and mast 6 cell differentiation. Genetic alterations of this gene, however, are not only associated with X-linked inherited erythroid or megakaryocytic disorders, but are also found in acquired myeloproliferative disorders. Each mutation is associated with a specific abnormality: point mutations that abrogate the ability of the amino-terminal zinc finger domain of the protein to bind either DNA or Fog1, a partner of Gata1, are found in inherited disorders. [7][8][9][10] On the other hand, frame shift and splice mutations encoding GATA1s, a protein lacking the amino-terminal domain, are associated not only with impaired inherited erythropoiesis, 11,12 but are also found in patients with megakaryocytic leukemia in Down syndrome, 13,14 in newborns with transient myeloproliferative syndromes, 15 and in one adult patient with megakaryocytic leukemia. 16 These observations suggest that, in addition to its effect on terminal differentiation, Gata1 might control the biologic properties of hematopoietic progenitor cells, predisposing them to accumulate secondary mutations in a multistep leukemogenic process. However, direct proof for a possible function of Gata1 in progenitor cells has not been provided as yet.We had previously described that hematopoietic tissues from mice carrying the hypomorphic Gata1 low mutation contain high numbers (ϳ10%) of "unique" progenitor cells that generate colonies composed of erythroblasts, megakaryocytes, and mast cells. 6 Predicted by the stochastic model of hematopoietic commitment, 17 such a trilineage progenitor has not been isolated prospectively as yet from the marrow of normal mice. In fact, antigenic profiling has prospectively divided normal murine progenitors into myeloid-and mast cell-restricted. The myeloid-restricted ones are further divided into granulomonocytic progenitors (GMPs), megakaryocytic-erythroid progenitors (MEPs), and common myeloid progenitors (CMPs). 18 GMPs correspond to cells previously defined, by functional clonogenesis, as colony-forming cells that generate in 7 days granulocytic, monomacrophagic and granulomonocytic colonies (CFU-Gs, CFU-Ms, and CFU-GMs). MEPs, on the other hand, include cells once functionally defined as those that generate megakaryocytic or erythroid colonies either in 3 days (CFU-MKs day3 and CFU-Es) or 7 days (CFU-MKs day7 and BFUEs). CMPs were functionally defined as multilineage progenitor cells, that is, those that generate colonies of multiple lineages after 12 to 15 days either in vitro (CFU-mix) or in vivo (spleen colony-forming cells, CFU-Ss day12 ). Mast cells are localized in extramedullary sites where they engage themselves in the process of allergic response and in the immune reaction against parasites. 19,20 As all the other hematopoietic cells, they derive from progenitor cells present in the marrow (and in the spleen) of ...

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

“…The frequency of stem/progenitor cells (CD117 pos ) in the marrow of Gata1 low mice was similar to that of normal animals ( Figure 4B, Table I and 11,44,45 ). However, because of a 5-fold reduction in marrow cellularity observed in these mice with disease progression, the total number of stem/progenitor cells in the marrow was calculated to be 5-fold lower than normal (Table I and 11,44 ).…”

“…Non-specific fluorescent signals were gated out with appropriate fluorochrome-conjugated isotype controls and dead cells were excluded by propidium iodide staining. Cells in the stem/progenitor cell (CD117 pos ) or megakaryocyte (CD61 pos ) gates were purified by sorting, as previously described 44,45 and were >90% pure upon FACS reanalysis.…”

“…CD117 expression identifies also stem/progenitor cells in the marrow of mice with the Gata1 low mutation 11,44 . CD34, however, is not an effective marker for identifying functional subpopulations from Gata1 low CD117 pos cells 45 . Therefore, for the purpose of this study, the levels of CXCR4 expression were analyzed on the entire CD117 pos cell population present in the marrow of wild type and Gata1 low littermates.…”

Mast cell transcriptional networks

“…Mast cell precursors from these mice proliferate abnormally and display defects in apoptosis (32;33). In addition, committed mast cell progenitors from these mice cannot be detected in the marrow, but mast cells can be derived from the megakaryocyte-erythroid progenitor population (34). A deletion of the proximal erythroid promoter of GATA-1 (GATA-1 "enfeebled") also results in reduced GATA-1 expression(35); these mice display reduction in mature mast cells in the skin (36).…”

“…Megakaryocyteerythroid progenitors derived from the common myeloid progenitor are restricted to develop into either megakaryocytes or erythroid cells. However, in GATA-1 "knockdown"/GATA-1 "low" mutant mice, in which GATA-1 expression is markedly reduced (16), megakaryocyteerythroid progenitors also can develop into mast cells (17). Similarly, a conditional deletion of the stem cell leukemia gene (SCL) also results in promiscuous development of mast cells from the megakaryocyte-erythroid progenitors population, suggesting that SCL and GATA-1 participate in regulating megakaryocyte-erythroid progenitors differentiation into mast cells (18) (Figure 1).…”