OncogenicGata1causes stage-specific megakaryocyte differentiation delay

Abstract

Scientific Category: Haematopoiesis and Stem Cells Key PointsGATA1s-induced stage-specific differentiation delay increases immature megakaryocytes in vivo and in vitro, during development.Differentiation delay is associated with increased numbers of cells in S-phase and reduced apoptosis. AbstractThe megakaryocyte/erythroid Transient Myeloproliferative Disorder (TMD) in newborns with Down Syndrome (DS) occurs when N-terminal truncating mutations of the hemopoietic transcription factor GATA1, that produce GATA1short protein (GATA1s), are acquired early in development. Prior work has shown that murine GATA1s, by itself, causes a transient yolk sac myeloproliferative disorder. However, it is unclear where in the hemopoietic cellular hierarchy GATA1s exerts its effects to produce this myeloproliferative state. Here, through a detailed examination of hemopoiesis from murine GATA1s ES cells and GATA1s embryos we define defects in erythroid and megakaryocytic differentiation that occur relatively in hemopoiesis.GATA1s causes an arrest late in erythroid differentiation in vivo, and even more profoundly in ES-cell derived cultures, with a marked reduction of Ter-119 cells and reduced erythroid gene expression. In megakaryopoiesis, GATA1s causes a differentiation delay at a specific stage, with accumulation of immature, kitexpressing CD41 hi megakaryocytic cells. In this specific megakaryocytic compartment, there are increased numbers of GATA1s cells in S-phase of cell cycle and reduced number of apoptotic cells compared to GATA1 cells in the same cell compartment. There is also a delay in maturation of these immature GATA1s megakaryocytic lineage cells compared to GATA1 cells at the same stage of differentiation. Finally, even when GATA1s megakaryocytic cells mature, they mature aberrantly with altered megakaryocyte-specific gene expression and activity of the mature megakaryocyte enzyme, acetylcholinesterase. These studies pinpoint the hemopoietic compartment where GATA1s megakaryocyte myeloproliferation occurs, defining where molecular studies should now be focussed to understand the oncogenic action of GATA1s.

Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model

“…In this study, we did not observe a significant increase in the number and proliferation of MK progenitors nor on the output of MKs defined as CD41 + CD42 + cells upon engineering of GATA1s. This is consistent with the effect of Gata1s on murine ES cells ( 13 ) and the recent observation showing that the increased MK output generated by GATA1s is due to a shift in HSC differentiation toward the MK lineage rather than to a direct effect on MK progenitors ( 18 , 19 ). However, our results showed a marked synergy between SMC3 +/– and GATA1s on both proliferation (e.g., increased MK progenitor number and size of MK colonies) and ploidization.…”

“…How GATA1s and these secondary mutations cooperate to induce AMKL and why this leukemia development requires a T21 and a fetal hematopoiesis remain unclear and need modeling approaches. Mouse models have been limited by only minor defects induced by Gata1s in late megakaryocyte (MK) differentiation ( 10 – 13 ). Thus, it was crucial to develop human models of DS-AMKL.…”

Zkscan3 affects erythroblast development by regulating the transcriptional activity of GATA1 and KLF1 in mice

“…Interestingly, GATA1 has been reported to have antiapoptotic functions (Aguirre et al 2010 ; Juban et al 2021 ). In current manuscript, we did not find statistical difference of erythroblast apoptosis between wild-type and knockout mice in the bone marrow and spleen (Fig.…”

Advances in molecular characterization of myeloid proliferations associated with Down syndrome

“…GATA1s promotes megakaryocytic progenitor expansion and disrupts megakaryocytic and erythroid differentiation ( Shimizu et al, 2009 ; Chlon et al, 2015 ; Banno et al, 2016 ; Juban et al, 2021 ). This appears to involve synergistic interactions with other leukemogenic molecules; for example, GATA1s increases expression of miRNA-486-5p, an erythroid oncogenic miRNA ( Shaham et al, 2015 ).…”

“…Evidence from a range of cellular and animal disease models confirmed that TAM is initiated by increased gene dosage from chromosome 21 acting in cooperation with GATA1s . GATA1s mutation alone disrupts differentiation of megakaryocytes and promotes expansion of myeloid and megakaryocytic progenitors, while production of aberrant megakaryoblasts is strengthened on the background of trisomy 21 ( Banno et al, 2016 ; Juban et al, 2021 ; Matsuo et al, 2021 ). TAM requires the synergy between trisomy 21 and GATA1s but leukemic transformation may be independent of trisomy 21 ( Wagenblast et al, 2021 ; Arkoun et al, 2022 ).…”