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<p>Developing an efficient and safe therapy necessitates a mechanistic understanding of the complex underlying pathology and manipulation of the multiple pathways at the molecular and genetic level. Network-based simulation of chronic myeloid leukemia (CML), a relatively well-understood cancer model, revealed the dynamics of simultaneously expressing pro-apoptotic BIM (Bcl-2 interacting mediator of cell death) and silencing pro-survival MCL-1 (myeloid cell leukemia-1) in combination with the breakpoint cluster region (BCR)-Abelson (ABL)-targeted tyrosine kinase inhibitor dasatinib. Viral/nonviral chimeric nanoparticles (ChNPs) composed of a BIM-expressing adeno-associated virus (AAV) core and a degradable polymeric shell that encapsulates MCL-1 siRNA (BIM/MCL-1 ChNPs) selectively killed BCR-ABL + CML cells in combination with dasatinib. In a mouse CML model, the BIM/MCL-1 ChNPs and dasatinib combination therapy suppressed proliferation of BCR-ABL + hematopoietic cells and prevented leukemic infiltration of organs. The enhanced anti-leukemic effect was further pronounced in an acute phase model of the disease. This study investigated a strategy of developing a versatile and tunable multimodal therapy assisted by a computational toolset that analyzes the molecular foundation of a disease and predicts therapeutic response. The interdisciplinary approach developed and validated in this study can be used in discovering new therapies for cancer and other diseases.</p> Graphical Abstract <p></p>

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Multimodal gene and targeted drug therapy for chronic myelogenous leukemia using BIM/MCL-1 chimeric nanoparticle: computational target analysis and therapeutic validation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月13日

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  • Margaret L. Lugin,
  • Winnie Lei,
  • Rebecca T. Lee,
  • Jee Young Chung,
  • Nicholas M. Katritsis,
  • Woochang Hwang,
  • Angela G. Fleischman,
  • Namshik Han,
  • Young Jik Kwon

摘要

Developing an efficient and safe therapy necessitates a mechanistic understanding of the complex underlying pathology and manipulation of the multiple pathways at the molecular and genetic level. Network-based simulation of chronic myeloid leukemia (CML), a relatively well-understood cancer model, revealed the dynamics of simultaneously expressing pro-apoptotic BIM (Bcl-2 interacting mediator of cell death) and silencing pro-survival MCL-1 (myeloid cell leukemia-1) in combination with the breakpoint cluster region (BCR)-Abelson (ABL)-targeted tyrosine kinase inhibitor dasatinib. Viral/nonviral chimeric nanoparticles (ChNPs) composed of a BIM-expressing adeno-associated virus (AAV) core and a degradable polymeric shell that encapsulates MCL-1 siRNA (BIM/MCL-1 ChNPs) selectively killed BCR-ABL + CML cells in combination with dasatinib. In a mouse CML model, the BIM/MCL-1 ChNPs and dasatinib combination therapy suppressed proliferation of BCR-ABL + hematopoietic cells and prevented leukemic infiltration of organs. The enhanced anti-leukemic effect was further pronounced in an acute phase model of the disease. This study investigated a strategy of developing a versatile and tunable multimodal therapy assisted by a computational toolset that analyzes the molecular foundation of a disease and predicts therapeutic response. The interdisciplinary approach developed and validated in this study can be used in discovering new therapies for cancer and other diseases.

Graphical Abstract