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Comment
. 2022 Jul 15;132(14):e161659.
doi: 10.1172/JCI161659.

Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome-associated leukemia

Edward J Evans Jr  1   2 , James DeGregori  1   2
Affiliations
Comment

Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome-associated leukemia

Edward J Evans Jr et al. J Clin Invest. .

Abstract

Individuals with Down syndrome (DS) have more than 100-fold increased risk of acute megakaryoblastic leukemia (AMKL), but its pathogenesis is poorly understood. In this issue of the JCI, Arkoun et al. engineered stepwise DS-AMKL-associated mutations in GATA1, MPL, and SMC3 in human induced pluripotent stem cell (iPSC) clones from individuals with DS to dissect how each mutation affects gene expression control and megakaryocytic differentiation. The authors showed that the mutations cooperatively promote progression from transient myeloproliferative disorder to DS-AMKL. This study highlights the importance of mutation order and context in the perturbations of transcriptional and differentiation pathways involved in the evolution of hematologic malignancies, which will be critical for the development of preventative and therapeutic interventions.

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Conflict of interest statement

Conflict of interest: JD serves as a member of the American Association of Cancer Research (AACR) Special Conferences Committee and the AACR Cancer Evolution Working Group Steering Committee and serves as an Executive Subcommittee member for the AACR Aging, Stress, and Cancer Task Force; is a co-chair and on the Steering Committee for the National Cancer Institute (NCI) and the National Institute on Aging (NIA) Onco-Aging Consortium; and is president of the International Society for Evolution, Ecology, and Cancer (ISEEC). JD also serves as associate editor at Molecular Cancer Research (AACR), editor-in-chief for Aging and Cancer (Wiley); associate editor at Evolution, Medicine, and Public Health (Oxford); and associate editor at Aging Cell (Wiley). JD is on the External Advisory Board at the University of Alabama O’Neal Comprehensive Cancer Center and is an External Advisory Board member at Moffitt Cancer Center and Mitotherapeutix. JD has a patent titled, “Use of tyrosine kinase inhibitor in cancer treatment” (US patent no. US10076520B2).

Figures

Figure 1
Figure 1. Progressive disruption in megakaryopoiesis in a model of DS-AMKL.
The GATA1s mutation in hematopoietic progenitors induced in T21 iPSCs impairs megakaryopoiesis and leads to inefficient platelet generation and a TMD-like state, at least in part mediated by reduced chromatin accessibility and expression at NFE2 target genes. Subsequent inactivation of the cohesion complex component SMC3 (SMC3+/–) further reduces chromatin accessibility and expression of NFE2 target genes, leading to impaired platelet formation and the progression of a more AMKL-like state.
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References

    1. Hasle H, et al. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet. 2000;355(9199):165–169. doi: 10.1016/S0140-6736(99)05264-2. - DOI - PubMed
    1. Zeller B, et al. Acute leukaemia in children with Down syndrome: a population–based Nordic study. Br J Haematol. 2005;128(6):797–804. doi: 10.1111/j.1365-2141.2005.05398.x. - DOI - PubMed
    1. Crispino JD. GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol. 2005;16(1):137–147. doi: 10.1016/j.semcdb.2004.11.002. - DOI - PubMed
    1. Roberts I, et al. GATA1–mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood. 2013;122(24):3908–3917. doi: 10.1182/blood-2013-07-515148. - DOI - PMC - PubMed
    1. McNulty M, Crispino JD. Acute megakaryocytic leukemia. Cold Spring Harb Perspect Med. 2020;10(2):a034884. doi: 10.1101/cshperspect.a034884. - DOI - PMC - PubMed

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