GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy

Abstract

Introduction: GATA1, the founding member of a family of transcription factors, plays important roles in the development of hematopoietic cells of several lineages. Although loss of GATA1 has been known to impair hematopoiesis in animal models for nearly 25 years, the link between GATA1 defects and human blood diseases has only recently been realized. Areas covered: Here the current understanding of the functions of GATA1 in normal hematopoiesis and how it is altered in disease is reviewed. GATA1 is indispensable mainly for erythroid and megakaryocyte differentiation. In erythroid cells, GATA1 regulates early stages of differentiation, and its deficiency results in apoptosis. In megakaryocytes, GATA1 controls terminal maturation and its deficiency induces proliferation. GATA1 alterations are often found in diseases involving these two lineages, such as congenital erythroid and/or megakaryocyte deficiencies, including Diamond Blackfan Anemia (DBA), and acquired neoplasms, such as acute megakaryocytic leukemia (AMKL) and the myeloproliferative neoplasms (MPNs). Expert Commentary: Since the first discovery of GATA1 mutations in AMKL, the number of diseases that are associated with impaired GATA1 function has increased to include DBA and MPNs. With respect to the latter, we are only just now appreciating the link between enhanced JAK/STAT signaling, GATA1 deficiency and disease pathogenesis.

Regulation of GATA1 levels in erythropoiesis

“…The second GATA1 knockdown mouse strain was generated by replacing an upstream enhancer region in the GATA1 gene locus with a neomycin resistance cassette . In these mice, known as GATA1 low mice, GATA1 expression levels were originally reported to be knocked down to 20%, although subsequent analyses have shown GATA1 mRNA reduced by as much as 100‐fold in orthochromatic erythroblasts ( and references therein). The majority of GATA1 low male mice die of anemia between embryonic stages E13.5 and E14.5.…”

“…Thus, downregulation or absence of full length GATA1 protein in erythroid precursors, either directly through mutations in the GATA1 gene itself or indirectly through defects in GATA1 mRNA translation or the breakdown of the HSP70/GATA1 protective axis, result in defective erythropoiesis and disease. This is an addition to hematological deficiencies or malignancies affecting other hematopoietic lineages, where downregulation or loss of the full length GATA1 protein play a causative role, for example, in primary myelofibrosis affecting the megakaryocytic lineage or in trisomy 21 associated transient myeloproliferative disorder (TMD), acute megakaryoblastic leukemia (AMKL), and clonal eosinophilia …”

“…Interestingly, GATA1 expression in the megakaryocytes of GATA1 low mice is completely abolished and the mice are born with severe thrombocytopenia, associated with the expansion of abnormal megakaryocytic progenitors that, at 10 months of age, develops into a myeloproliferative condition characterized by fibrosis of the bone marrow, closely resembling primary myelofibrosis. 126,127 GATA1 low mice also have defects in mast cell differentiation, as evidenced by the amplification of mast cell progenitors, increased apoptotic precursors and defective differentiation of mature cells. 128 These observations provide yet more evidence for the necessity of maintaining appropriate GATA1 levels to support balanced hematopoiesis.…”

“…This is an addition to hematological deficiencies or F I G U R E 2 Model of GATA1 protein level regulation during erythroid maturation. Summary of the different mechanisms regulating GATA1 protein abundance, which leads to disease when deregulated malignancies affecting other hematopoietic lineages, where downregulation or loss of the full length GATA1 protein play a causative role, for example, in primary myelofibrosis affecting the megakaryocytic lineage 126 or in trisomy 21 associated transient myeloproliferative disorder (TMD), acute megakaryoblastic leukemia (AMKL), and clonal eosinophilia. 156,157 Interestingly enough, a balanced erythropoietic production is disturbed in the presence of subjacent inflammation, a phenomenon that has been named as anemia of inflammation or anemia of chronic disease.…”

Novel targets to cure primary myelofibrosis from studies on Gata1low mice

“…The discovery of the mutations that drive the development of MPNs prompted the development of mutation‐specific mouse models (reviewed in Reference ). These mutants rapidly develop a PV and/or ET phenotype, which eventually evolves in myelofibrosis, and are considered models for secondary myelofibrosis.…”