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December 8, 2025BloodOpen Access

Mechanistic dissection of venetoclax sensitivity in AML through single-molecule BCL2 protein complex profiling and mutation-specific apoptotic rewiring

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Authors

LGLilly GuEKEun‐Young KimHLHong-Won Lee

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Overview

Mechanistic dissection reveals that venetoclax and hypomethylating agents drive diverse responses in AML, highlighting protein interactions.

Key Points

  • To uncover the apoptotic signaling mechanisms underlying venetoclax and hypomethylating agents therapy in AML patients.
  • Employed single-molecule protein interaction detection (SPID) for high-resolution imaging of protein interactions.
  • Quantified BCL2-family protein-protein interactions in pre-treatment and on-treatment samples from AML patients.
  • Analyzed mutation-specific apoptotic rewiring using targeted sequencing data alongside PPI measurements.
  • Identified differential responses to venetoclax therapy based on the presence of FLT3-ITD and other mutations.
  • Demonstrated that FLT3-ITD mutations significantly alter anti-apoptotic complex formation and apoptotic dynamics.
  • Found that responders experienced effective apoptotic engagement while non-responders exhibited persistent BCL2–BAX complexes.

Cite This Study

Gu et al. (2025) studied this question.

synapsesocial.com/papers/69362f514fa91c937236d95chttps://doi.org/10.1182/blood-2025-341
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Also Consider

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

  1. 1Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy2026 · 2 citations
  2. 2Single-cell transcriptomic insights into venetoclax response and resistance in secondary AML evolving from MDS2025
  3. 3IDH1 mutation predicts response and survival in treatment-naïve Acute Myeloid Leukemia patients receiving with venetoclax with a hypomethylating agent2025
  4. 4Antiapoptotic BCL2 family proteins BCL-XL and MCL1 as factors predicting resistance against venetoclax plus azacitidine for patients with newly diagnosed acute myelogenous leukemia2026 · 1 citations
  5. 5Venetoclax dosages, BH3 profiling, and bcl-2 expression predict response to azacitidine + venetoclax regimen in first line AML not eligible to intensive chemotherapy: First results of venetacible study2025 · 1 citations