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December 8, 2025Blood

Single-cell transcriptomic insights into venetoclax response and resistance in secondary AML evolving from MDS

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Authors

SPSilvia ParkJJJinho JangJLJaewoong Lee

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Overview

Single-cell analysis reveals immunological and metabolic drivers of venetoclax resistance in secondary AML, suggesting new therapeutic strategies.

Key Points

  • Investigate mechanisms of venetoclax resistance in secondary AML arising from myelodysplastic syndromes using single-cell RNA sequencing.
  • Performed single-cell RNA sequencing on 279,211 bone marrow-derived cells from 25 samples of 14 s-AML patients.
  • Analyzed differential transcriptomic signatures across hematopoietic stem/progenitor cells, T/NK cells, and myeloid compartments.
  • Validated findings through flow cytometry, RT-qPCR, and experiments with a venetoclax-resistant AML cell line.
  • Identified MYC activation and PHGDH-driven serine biosynthesis as key resistance mechanisms in non-responders.
  • Non-responders showed metabolic pathway upregulation and immune dysregulation, including T cell depletion.
  • Enrichment of immunosuppressive myeloid populations correlated with resistance observed in the study.

Cite This Study

Park et al. (2025) studied this question.

synapsesocial.com/papers/69362f4b4fa91c937236d795https://doi.org/10.1182/blood-2025-2061
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