Inherent genome instability underlies trisomy 21-associated myeloid malignancies - PubMed (original) (raw)

. 2024 Mar;38(3):521-529.

doi: 10.1038/s41375-024-02151-8. Epub 2024 Jan 20.

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Inherent genome instability underlies trisomy 21-associated myeloid malignancies

Chun-Chin Chen et al. Leukemia. 2024 Mar.

Abstract

Constitutional trisomy 21 (T21) is a state of aneuploidy associated with high incidence of childhood acute myeloid leukemia (AML). T21-associated AML is preceded by transient abnormal myelopoiesis (TAM), which is triggered by truncating mutations in GATA1 generating a short GATA1 isoform (GATA1s). T21-associated AML emerges due to secondary mutations in hematopoietic clones bearing GATA1s. Since aneuploidy generally impairs cellular fitness, the paradoxically elevated risk of myeloid malignancy in T21 is not fully understood. We hypothesized that individuals with T21 bear inherent genome instability in hematopoietic lineages that promotes leukemogenic mutations driving the genesis of TAM and AML. We found that individuals with T21 show increased chromosomal copy number variations (CNVs) compared to euploid individuals, suggesting that genome instability could be underlying predisposition to TAM and AML. Acquisition of GATA1s enforces myeloid skewing and maintenance of the hematopoietic progenitor state independently of T21; however, GATA1s in T21 hematopoietic progenitor cells (HPCs) further augments genome instability. Increased dosage of the chromosome 21 (chr21) gene DYRK1A impairs homology-directed DNA repair as a mechanism of elevated mutagenesis. These results posit a model wherein inherent genome instability in T21 drives myeloid malignancy in concert with GATA1s mutations.

© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

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References

    1. Marlow EC, Ducore J, Kwan ML, Cheng SY, Bowles EJA, Greenlee RT, et al. Leukemia Risk in a Cohort of 3.9 Million Children with and without Down Syndrome. J Pediatr. 2021;234:172–80 e3. - PubMed - PMC
    1. Roberts I, Alford K, Hall G, Juban G, Richmond H, Norton A, 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;122:3908–17. - PubMed - PMC
    1. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002;32:148–52. - PubMed
    1. Labuhn M, Perkins K, Matzk S, Varghese L, Garnett C, Papaemmanuil E, et al. Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with down syndrome. Cancer Cell. 2019;36:123–38.e10. - PubMed - PMC
    1. Laurent AP, Kotecha RS, Malinge S. Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome. Leukemia. 2020;34:1984–99. - PubMed - PMC

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