Abnormalities of GATA-1 in Megakaryocytes from Patients with Idiopathic Myelofibrosis

Abstract

The abnormal megakaryocytopoiesis associated with idiopathic myelofibrosis (IM) plays a role in its pathogenesis. Because mice with defective expression of transcription factor GATA-1 (GATA-1 low mutants) eventually develop myelofibrosis, we investigated the occurrence of GATA-1 abnormalities in IM patients. CD34 ؉ cells were purified from 12 IM patients and 8 controls; erythroblasts and megakaryocytes were then obtained from unilineage cultures of CD34 ؉ cells. Purified CD61 ؉ , GPA ؉ , and CD34 ؉ cells from IM patients contained levels of GATA-1, GATA-2, and FOG-1 mRNA, as well as of GATA-2 protein, that were similar to controls. In contrast, CD61 ؉ cells from IM patients contained significantly reduced GATA-1 protein. Furthermore, 45% of megakaryocytes in biopsies from IM patients did not stain with anti-GATA-1 antibody, as compared to controls (2%), essential thrombocythemia (4%), or polycythemia vera (11%) patients. Abnormalities in immunoreactivity for FOG-1 were not found, and no mutations in GATA-1 coding sequences were found. The presence of GATA-1 neg megakaryocytes in bone marrow biopsies was independent of the Val617Phe JAK2 mutation, making it unlikely that a downstream functional relationship exists. We conclude that megakaryocytes from IM patients have reduced GATA-1 content, possibly contributing to disease pathogenesis as in the GATA-1 low mice and also representing a novel IM-associated marker. (Am J Pathol 2005, 167:849 -858)

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

“…Since GATA1 is known to regulate transcription in late megakaryopoiesis (whereas GATA2 is more important in the early stages) [1], XLTT and PMF megakaryocytes low in GATA1 protein expression might represent immature forms [8,28]. Intriguingly, GATA1 mRNA expression in megakaryocytes [28], blood CD341 progenitors [29], and mononuclear BM cells [30] were found to be similar in PMF compared with control subjects. Novel information from the NCBI/GEO database has even shown higher GATA1 mRNA expression in whole blood and granulocytes from PMF patients compared with controls (GEO Accession: GSE26049 and GSE54646, unpublished results) [31,32].…”

Myelofibrosis with Myeloid Metaplasia: New Developments in Pathogenesis and Treatment

“…One group has reported no changes in GATA-1 expression in CD34 + cells isolated from patients with myelofibrosis (37). In contrast, another group has just reported in abstract form that GATA-1 levels are lower in progenitor cells isolated from patients with MMM (38). The two groups also report conflicting results in relation to friend of GATA-1 (FOG-1), an essential co-factor for GATA-1 function as a transcription factor.…”

A quantitative assay for JAK2V617F mutation in myeloproliferative disorders by ARMS-PCR and capillary electrophoresis

“…The reported frequency of JAK2 V617F mutation is around 80% (range, 65-100%) in PV, 40% (range, 23-57%) in ET and 55% (range, 35-95%) in IM patients. [5][6][7][8][10][11][12][13][14][15] JAK2 V617F mutation is found in either the heterozygote or the homozygote status, the latter arising from mitotic recombination; [5][6][7][8] there are significant differences in the incidence of homozygosity, which involves about 30% of patients in PV and IM and less than 4% in ET.…”

“…The reported frequency of JAK2 V617F mutation is around 80% (range, 65-100%) in PV, 40% (range, 23-57%) in ET and 55% (range, 35-95%) in IM patients. [5][6][7][8][10][11][12][13][14][15] JAK2 V617F mutation is found in either the heterozygote or the homozygote status, the latter arising from mitotic recombination; [5][6][7][8] there are significant differences in the incidence of homozygosity, which involves about 30% of patients in PV and IM and less than 4% in ET.Whether the presence of the mutation itself can help in identifying biologically and/or clinically distinct subgroups of patients is largely unsettled. 16 In fact, in some of the series published until now, the presence of the mutation has been associated with longer disease duration, propensity to myelofibrosis development (in PV or ET patients) or to leukemia transformation, higher risk of thrombotic complications, advanced age or greater requirement for therapy, whereas others have reported the opposite or no correlation at all; 5,7,8,14,15,17 also, a poorer overall survival has been reported in JAK2 V617F IM patients.…”