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September 5, 2026Blood Cancer Discovery

Germline noncoding risk variants influence clonal hematopoiesis through altered hematopoietic enhancer activity

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Authors

TNTrieu NguyenAlbert Einstein College of MedicineJJJessica JeejanAlbert Einstein College of MedicineTITakeshi IwasakiKyoto University

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Implication

Experimental functional screen reveals noncoding risk alleles alter enhancer activity in hematopoietic stem cells, indicating a mechanistic driver of clonal expansion.

Key Points

  • To identify functional noncoding risk variants associated with clonal hematopoiesis of indeterminate potential and determine how they alter hematopoietic enhancer activity.
  • Screened 1,374 noncoding variants from 51 clonal hematopoiesis loci using a massively parallel reporter assay in CD34+ MUTZ-3 cells.
  • Validated regulatory activity using targeted genome editing and reporter assays in primary human hematopoietic stem and progenitor cells.
  • Identified 87 functional regulatory variants across 32 loci that alter enhancer activity, confirming regulation of NKD2, FLT3, and MSI2.
  • Increased MSI2 expression, reflecting the risk allele mechanism, significantly promotes the clonal expansion of TET2-deficient hematopoietic stem and progenitor cells.

Cite This Study

Nguyen et al. (2026) studied this question.

synapsesocial.com/papers/6a9bd4726b95aff0620ec37chttps://doi.org/10.1158/2643-3230.bcd-26-0046
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Assessing germline noncoding risk variants impacting clonal hematopoiesis using a massively parallel reporter assay2025
  2. 2Clonal Hematopoiesis of Indeterminate Potential and Cardiometabolic Disease: Challenges, Controversies and Future Perspectives2025 · 8 citations
  3. 3Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation2024 · 3 citations
  4. 4Clonal hematopoiesis associates with prevalent and incident cardiometabolic disease in a cardiac catheterization cohort2026 · 2 citations
  5. 5Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions2026