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Updated: May 22, 2026
Identifying Bone Marrow Microenvironmental Populations in Myelodysplastic Syndrome and Acute Myeloid Leukemia
Published on: November 10, 2023
Molecular biology of chronic myeloid leukemia
1Department of Pharmacology, Tokyo Women's Medical University, Japan. ymaru@research.twmu.ac.jp
Abstract:
Detailed information on the crystal structure of the pharmacologically targeted domains of the BCR-ABL molecule and on its intracellular signaling, which are potentially involved in growth, anti-apoptosis, metabolism and stemness, has made the study of chronic myeloid leukemia the most successful field in tumor biology. However, we now face the issue of drug resistance due to deregulation in the quality control of both DNA and protein. BCR-ABL is basically a misfolded protein with intrinsically disordered regions, which not only produces endoplasmic reticulum stress followed by unfolded protein response in some settings, but also conformational plasticity that may affect the structure of the whole molecule. The intercellular signaling derived from the leukemic cell microenvironment may influence the intracellular responses that take place in a manner both dependent on and independent of BCR-ABL tyrosine kinase activity.
Insights
Drug resistance in chronic myeloid leukemia (CML) arises from protein quality control issues. Misfolded BCR-ABL protein exhibits conformational flexibility, impacting cellular signaling and treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chronic myeloid leukemia (CML) research has advanced significantly due to understanding BCR-ABL molecular targets and signaling pathways.
- Drug resistance is a major challenge in CML treatment, linked to impaired DNA and protein quality control mechanisms.
Purpose of the Study:
- To explore the role of protein misfolding and conformational plasticity in BCR-ABL, contributing to CML drug resistance.
- To investigate how microenvironmental signaling influences intracellular responses in CML cells.
Main Methods:
- Analysis of BCR-ABL molecular structure and intracellular signaling pathways.
- Investigation of endoplasmic reticulum stress and unfolded protein response in CML.
Main Results:
- BCR-ABL is identified as a misfolded protein with intrinsically disordered regions, exhibiting conformational plasticity.
- This plasticity can alter the molecule's structure and influence cellular processes like growth, anti-apoptosis, metabolism, and stemness.
- Intercellular signaling from the microenvironment modulates BCR-ABL-dependent and independent intracellular responses.
Conclusions:
- Protein misfolding and conformational flexibility of BCR-ABL are key factors in CML drug resistance.
- Understanding these molecular dynamics and microenvironmental interactions is crucial for developing more effective CML therapies.
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