Contribution of GATA1 dysfunction to multi‐step leukemogenesis

Abstract

In mammals, hematopoietic homeostasis is maintained by a fine-tuned balance among the self-renewal, proliferation, differentiation and survival of hematopoietic stem cells and their progenies. Each process is also supported by the delicate balance of the expression of multiple genes specific to each process. GATA1 is a transcription factor that comprehensively regulates the genes that are important for the development of erythroid and megakaryocytic cells. Accumulating evidence supports the notion that defects in GATA1 function are intimately linked to hematopoietic disorders. In particular, the somatic mutation of the GATA1 gene, which leads to the production of N-terminally truncated GATA1, contributes to the genesis of transient myeloproliferative disorder and acute megakaryoblastic leukemia in infants with Down syndrome. Similarly, a mutation in the GATA1 regulatory region that reduces GATA1 expression is involved in the onset of erythroid leukemia in mice. In both cases, the accumulation of immature progenitor cells caused by GATA1 dysregulation underlies the pathogenesis of the leukemia. This review provides a summary of multi-step leukemogenesis with a focus on GATA1 dysfunction.

Aberrant DNA methylation profile of chronic and transformed classic Philadelphia-negative myeloproliferative neoplasms

“…40 Beside the NF-κB pathway, in agreement with a recent report, 36 in our methylated genes data set we found an enrichment of binding sites for transcription factors such as GATA1 or SP1 that are altered in hematologic malignancies. 41 These results suggest that the inappropriate methylation of CpGs may prevent proper binding of these transcription factors, indirectly altering their participation in the transcription of necessary genes.…”

Regulation of GATA1 levels in erythropoiesis

“…By contrast, GATA1‐null cells in a heterozygous female background would be eliminated by apoptosis. Thus, additional genetic events that may occur in the proliferating GATA1.05 progenitor population can lead to leukemic transformation . Interestingly, older GATA1.05 mice also develop CD19+ B‐cell leukemia through a leukemogenic mechanism that is not yet understood, but may be related to lineage commitment skewing toward lymphoid fates by proliferating progenitors expressing low levels of GATA1 …”

Regulation of GATA-binding Protein 2 Levels via Ubiquitin-dependent Degradation by Fbw7

“…GATA2 participates in proliferation and differentiation of hematopoietic cell lineages. Although GATA1 is also expressed in erythroid precursors, megakaryocytes, and eosinophils (34), the identity of aa among GATA3 or GATA2 and GATA1 is high in zinc finger domains but low in other regions. It was reported that mutations of one allele of GATA2 participate in hematopoietic or immune system diseases (35,36).…”