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ATRA-induced cellular differentiation and CD38 expression inhibits acquisition of BCR-ABL mutations for CML acquired

Zhiqiang Wang1, Zheng Liu2, Xiwei Wu2

  • 1Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.

Plos Genetics
|June 27, 2014
PubMed

Insights

All-trans-retinoic acid (ATRA) prevents chronic myeloid leukemia (CML) cells from becoming resistant to tyrosine kinase inhibitors (TKIs). ATRA blocks BCR-ABL mutations by reducing DNA damage repair, offering a potential combination therapy for CML.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Acquired resistance to targeted therapies like tyrosine kinase inhibitors (TKIs) is a significant challenge in chronic myeloid leukemia (CML) treatment.
  • The precise mechanisms driving TKI resistance in CML, particularly genetic mutations, remain incompletely understood.
  • Genetic mutations, such as the T315I BCR-ABL mutation, are known to confer resistance, but other pathways may also contribute.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying acquired resistance to TKIs in chronic myeloid leukemia (CML).
  • To explore the potential of all-trans-retinoic acid (ATRA) in overcoming or preventing TKI resistance in CML.
  • To elucidate the role of myeloid differentiation, CD38, NAD+ levels, and SIRT1 in TKI resistance.

Main Methods:

  • Comparative gene expression analysis of TKI-sensitive (KCL-22) and TKI-resistant (KCL-22M) CML cells.
  • Induction of myeloid differentiation using all-trans-retinoic acid (ATRA) in TKI-resistant CML models.
  • Measurement of CD38 expression, intracellular nicotinamide adenine dinucleotide (NAD+) levels, and SIRT1 deacetylase activity.
  • Assessment of DNA damage repair efficacy and BCR-ABL mutation acquisition following ATRA treatment.

Main Results:

  • Resistant KCL-22M cells exhibited activated multiple drug resistance pathways and reduced myeloid differentiation gene expression.
  • Forced myeloid differentiation with ATRA successfully blocked BCR-ABL mutations and TKI resistance in vitro.
  • ATRA treatment increased CD38 expression, leading to decreased intracellular NAD+ levels and inhibited SIRT1 activity.
  • ATRA suppressed DNA damage repair, thereby preventing the acquisition of BCR-ABL mutations and TKI resistance.

Conclusions:

  • Acquired TKI resistance in CML involves complex mechanisms beyond just BCR-ABL mutations, including alterations in drug resistance pathways and myeloid differentiation.
  • All-trans-retinoic acid (ATRA) demonstrates significant potential in preventing TKI resistance by promoting myeloid differentiation and modulating the NAD+/SIRT1 pathway.
  • Combining ATRA with TKIs may offer a promising therapeutic strategy for managing CML, especially in advanced stages or cases with resistance.

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