Inherent genome instability underlies trisomy 21-associated myeloid malignancies.

Jan 22, 2024

Experts: Chun-Chin Chen,Rebecca E Silberman,Duanduan Ma,Jennifer A Perry,Delan Khalid,Yana Pikman,Angelika Amon,Michael T Hemann,R Grant Rowe

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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ABOUT THE EXPERTS

Chun-Chin Chen,Rebecca E Silberman,Duanduan Ma,Jennifer A Perry,Delan Khalid,Yana Pikman,Angelika Amon,Michael T Hemann,R Grant Rowe

Chun-Chin Chen

Stem Cell Transplantation Program, Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Rebecca E Silberman

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

RA Capital, Boston, MA, USA.

Duanduan Ma

The Barbara K. Ostrom (1978) Bioinformatics and Computing Facility, Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Jennifer A Perry

Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Delan Khalid

Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Yana Pikman

Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA.

Harvard Medical School, Boston, MA, USA.

Angelika Amon

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.

Michael T Hemann

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. hemann@mit.edu.

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. hemann@mit.edu.

R Grant Rowe

Stem Cell Transplantation Program, Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA. grant_rowe@dfci.harvard.edu.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA. grant_rowe@dfci.harvard.edu.

Harvard Medical School, Boston, MA, USA. grant_rowe@dfci.harvard.edu.