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Induction of hyperproliferative fetal megakaryopoiesis by an N‐terminally truncated GATA1 mutant
Author(s) -
Shimizu Ritsuko,
Kobayashi Eri,
Engel James Douglas,
Yamamoto Masayuki
Publication year - 2009
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2009.01338.x
Subject(s) - gata1 , biology , acute megakaryoblastic leukemia , megakaryocyte , haematopoiesis , mutant , leukemia , cancer research , microbiology and biotechnology , immunology , genetics , stem cell , gene
Two GATA1‐related leukemias have been described: one is an erythroleukemia that develops in mice as a consequence of diminished expression of wild‐type GATA1, whereas the other is an acute megakaryoblastic leukemia (AMKL) that arises in Down syndrome children as a consequence of somatic N‐terminal truncation (ΔNT) of GATA1 . We discovered that mice expressing the shortened GATA1 protein (ΔNTR mice) phenocopies the human transient myeloproliferative disorder (TMD) that precedes AMKL in Down syndrome children. In perinatal livers of the ΔNTR mutant mice, immature megakaryocytes accumulate massively, and this fraction contains cells that form hyperproliferative megakaryocytic colonies. Furthermore, showing good agreement with the clinical course of TMD in humans, ΔNTR mutant mice undergo spontaneous resolution from the massive megakaryocyte accumulation concomitant with the switch of hematopoietic microenvironment from liver to bone marrow/spleen. These results thus demonstrate that expression of the GATA1/Gata1 N‐terminal deletion mutant per se induces hyperproliferative fetal megakaryopoiesis. This mouse model serves as an important means to clarify how impaired GATA1 function contributes to the multi‐step leukemogenesis.