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<p>Core-binding factor (CBF) leukemias, including inv(16) AML, involve RUNX1/CBFβ chromosomal rearrangements that generate oncogenic fusion proteins. In inv(16) AML, the CBFβ–SMMHC fusion (CBFB–MYH11) dominantly perturbs RUNX1 by sequestering it in aberrant, high-affinity complexes. Structural studies reveal that CBFβ–SMMHC binds the RUNX1 Runt domain with higher affinity than wild-type CBFβ, aided by a second RUNX1-binding site in its SMMHC tail. This altered interface underlies the fusion’s dominant-negative disruption of RUNX1 target-gene regulation. Chemical probes have been developed to disrupt this interface; notably, the bivalent inhibitor AI-10-49 selectively binds CBFβ–SMMHC, displacing RUNX1 and restoring RUNX1 transcriptional function. AI-10-49 delays leukemia progression in murine inv(16) models and induces apoptosis in human inv(16) AML cells. Mechanistically, uncoupling RUNX1 from CBFβ–SMMHC liberates RUNX1 to repress oncogenic programs: for example, RUNX1 rebinds distal MYC enhancers and recruits polycomb factors (RING1B) in place of SWI/SNF (BRG1) to silence MYC, triggering leukemia cell apoptosis. These chromatin and transcriptional consequences underscore how CBFβ–SMMHC sustains leukemic transcriptional programs. Importantly, combining CBFβ–SMMHC inhibitors with BET bromodomain inhibitors synergistically eradicates inv(16) leukemia in preclinical models. Together, these insights into the structural basis and functional role of the CBFβ–SMMHC–RUNX1 interface highlight protein–protein interaction disruption as a promising translational strategy in core-binding factor leukemia therapy.</p>

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Disrupting the CBFβ-SMMHC-RUNX1 oncogenic protein–protein interaction in inv(16) AML: from fusion biology to targeted therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Emadeldin M. Kamel,
  • Sally Mostafa Khadrawy,
  • Mohamed A. M. Ali,
  • Noha A. Ahmed,
  • Saleh Alkhedhairi,
  • Faris F. Aba Alkhayl,
  • Al Mokhtar Lamsabhi

摘要

Core-binding factor (CBF) leukemias, including inv(16) AML, involve RUNX1/CBFβ chromosomal rearrangements that generate oncogenic fusion proteins. In inv(16) AML, the CBFβ–SMMHC fusion (CBFB–MYH11) dominantly perturbs RUNX1 by sequestering it in aberrant, high-affinity complexes. Structural studies reveal that CBFβ–SMMHC binds the RUNX1 Runt domain with higher affinity than wild-type CBFβ, aided by a second RUNX1-binding site in its SMMHC tail. This altered interface underlies the fusion’s dominant-negative disruption of RUNX1 target-gene regulation. Chemical probes have been developed to disrupt this interface; notably, the bivalent inhibitor AI-10-49 selectively binds CBFβ–SMMHC, displacing RUNX1 and restoring RUNX1 transcriptional function. AI-10-49 delays leukemia progression in murine inv(16) models and induces apoptosis in human inv(16) AML cells. Mechanistically, uncoupling RUNX1 from CBFβ–SMMHC liberates RUNX1 to repress oncogenic programs: for example, RUNX1 rebinds distal MYC enhancers and recruits polycomb factors (RING1B) in place of SWI/SNF (BRG1) to silence MYC, triggering leukemia cell apoptosis. These chromatin and transcriptional consequences underscore how CBFβ–SMMHC sustains leukemic transcriptional programs. Importantly, combining CBFβ–SMMHC inhibitors with BET bromodomain inhibitors synergistically eradicates inv(16) leukemia in preclinical models. Together, these insights into the structural basis and functional role of the CBFβ–SMMHC–RUNX1 interface highlight protein–protein interaction disruption as a promising translational strategy in core-binding factor leukemia therapy.