Fig. 2

Defects in megakaryocyte maturation due to GATA1s mutation are crucial for leukemia development. (A) Platelet counts (left) and hematocrit values (right) of ΔNTR-H and ΔNTR-M embryos at E18.5. (B-D) Evaluation of proplatelet formation of the rescued mice. Fetal livers at E17.5 or E18.5 (B) and bone marrows at postnatal day 34 (P34) to P47 (D) were examined. Fetal livers obtained from 2 to 3 wild-type littermates were combined and used as controls. (C) Representative images of megakaryocytes forming proplatelets in wild type (upper panel) and those lacking proplatelet extensions in ΔNTR-M (lower panel) mice. The cytoplasm of megakaryocytes was visualized by green fluorescence protein produced under the regulation of G1HRD [7]. Results from 5 wild-type control samples obtained from each combined sample, 5 ΔNTR-H and 4 ΔNTR-M fetal livers are presented in (B) and 6 wild-type, 5 ΔNTR-H and 5ΔNTR-M bone marrow samples are presented in (D). The data was analyzed using the Mann-Whitney U test. *; P < 0.05, **; P < 0.01. (E) A model depicting the development of AMKL in ΔNTR-M mice. Wild-type GATA1 supports the balance between proliferation and maturation of megakaryocytes during the process of platelet production (upper panel). Exclusive expression of GATA1s skews immature progenitors toward a proliferation-dominant state (middle and lower panels). However, megakaryocyte progenitors in the bone marrow with more abundant GATA1s expression have the capacity to terminally differentiate (middle panel), while those bearing less abundant GATA1s expression are more likely to remain in an immature stage and harbor an increased chance to acquire additional gene mutations (lower panel)