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December 8, 2025BloodOpen Access

Human HSPCs CRISPR-engineered to endogenously express oncogenic NRAS generate a transplantable lethal myeloid malignancy targetable with novel RAS therapeutics

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Authors

SLShirley LiuJCJames S. ChavezTKThomas Köhnke

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Overview

CRISPR-engineering HSPCs drove myeloid neoplasms in mice, suggesting RAS inhibitors may reduce malignancy risks.

Key Points

  • To characterize the impact of endogenous NRAS expression in human HSPCs on myeloid malignancy development and evaluate RAS inhibitor efficacy.
  • Generated a model of endogenous NRAS expression using CRISPR in human cord blood CD34+ HSPCs.
  • Engineered HSPCs were transplanted into immunocompromised mice for assessment of malignancy.
  • Evaluated the effects of RMC-7977 on colony formation and proliferation of NRAS-mutant HSPCs.
  • Mice with endoNRASG12D showed delayed onset of cytopenias and myeloid neoplasms compared to UBC-NRASG12D mice.
  • EndoNRASG12D led to a median survival of 99 days versus 31 days for UBC-NRASG12D.
  • RMC-7977 treatment significantly decreased colony formation in NRAS-mutant HSPCs.

Cite This Study

Liu et al. (2025) studied this question.

synapsesocial.com/papers/693624d74fa91c937236d107https://doi.org/10.1182/blood-2025-5004
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Also Consider

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

  1. 1RAS G12 and Q61 codon mutations confer distinct disease characteristics in Acute Myeloid Leukemia and exhibit differential response to RAS(ON) inhibitor RMC-7977.2025
  2. 2KRAS G12D Blocks Erythroid Differentiation and Promotes Inflammatory Pathways at the Single Cell Level in Myeloid Malignancies 22515712026
  3. 3Modeling KRAS mutations in KMT2A::MLLT3 acute myeloid leukemia promotes leukemic progression and transcriptional rewiring2026
  4. 4Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells2024
  5. 5Cooperative activation of NF-κB by inv(3)/t(3;3) and NRAS mutations drives myeloid leukemogenesis2025