Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants
The role of germline CHEK2 variants in hematopoietic malignancies (HMs) is poorly understood. We examined pathogenic/likely pathogenic (P/LP) CHEK2 variants in patients with hereditary HMs (HHMs), a solid tumor risk cohort, public datasets, and a knock-in mouse model. In the HHM cohort, 57 probands had germline P/LP CHEK2 variants, mostly p.I157T (53%, 30/57). Among CHEK2 p.I157T carriers, 43% (19/44) had myeloid malignancies, 32% (14/44) had lymphoid malignancies, and 2% (1/44) had both. Among those with other germline P/LP CHEK2 alleles, 36% (13/36) had myeloid malignancies, 28% (10/36) had lymphoid malignancies, and 6% (2/36) had both. CHEK2 p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68-10.73, P < 0.001). In a solid tumor risk cohort, 36% (15/42) of CHEK2 p.I157T patients had a HM family history. A genome wide association study showed enrichment of CHEK2 loss-of-function variants with myeloid leukemia (P = 5.78e<sup>-7</sup>). In public acute myeloid leukemia (AML) datasets, 1% (16/1348) of patients had P/LP CHEK2 variants. In a public myelodysplastic neoplasms (MDS) dataset, 2% (5/214) had P/LP CHEK2 variants. Chek2 p.I161T mice, homologous to human p.I157T, had worse survival as heterozygotes (P = 0.037) or homozygotes (P = 0.005), with fewer Lin-CD34+ and Lin-cKit+ cells. Our data suggest P/LP CHEK2 variants are HHM risk alleles.
Authors
- Afaf E.G. Osman (ORCID: https://orcid.org/0000-0002-3688-4683)
- Jason X. Cheng (ORCID: https://orcid.org/0000-0002-4626-770X)
- Imo J. Akpan (ORCID: https://orcid.org/0000-0002-6793-599X)
- Michael W. Drazer (ORCID: https://orcid.org/0000-0002-8171-4106)
- Jennie Vagher (ORCID: https://orcid.org/0009-0004-5818-6589)
- Edward Chew (ORCID: https://orcid.org/0000-0002-1075-6616)
- Joshua Bridgers (ORCID: https://orcid.org/0000-0002-5257-6277)
- Ryan J. Stubbins (ORCID: https://orcid.org/0000-0002-4718-5212)
- Anase Asom (ORCID: https://orcid.org/0000-0001-7049-1536)
- Lucy A. Godley (ORCID: https://orcid.org/0000-0003-1914-9158)
- Soma Das (ORCID: https://orcid.org/0000-0002-7146-7869)
- Ashwin Koppayi (ORCID: https://orcid.org/0000-0001-9956-1374)
- Stephen Arnovitz (ORCID: https://orcid.org/0000-0001-5307-8694)
- Aly Karsan (ORCID: https://orcid.org/0000-0001-6753-892X)
- Melody Perpich
- Madeline Pies
- Hatice Basdag
- Courtnee V. Rodgers
Institutions
- The Royal Melbourne Hospital (AU)
- University of British Columbia (CA)
- University of Utah (US)
- Columbia University Irving Medical Center (US)
- University of Chicago (US)
- Canada's Michael Smith Genome Sciences Centre (CA)
- Leukemia & Lymphoma Society of Canada (CA)
- Austin Health (AU)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Leukemia
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1038/s41375-025-02635-1
- Citations
- 9
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 15.93
Funders
- V Foundation for Cancer Research
- Cancer Research Foundation
- Leukemia and Lymphoma Society
- Northwestern University
- Leukemia and Lymphoma Society of Canada
- Veski
- Terry Fox Foundation
- Canadian Institutes of Health Research