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Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia: From Patient Material To Sequence Interpretation
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Gene expression and linkage analysis implicate CBLB as a mediator of rituximab resistance

J Jack1,2, G W Small3, C C Brown4

  • 1Department of Statistics, North Carolina State University, Raleigh, NC, USA.

The Pharmacogenomics Journal
|December 6, 2017
PubMed

Insights

Understanding how cancer patients develop resistance to therapeutic monoclonal antibodies (mAbs) is crucial. This study identifies novel genes, like CBLB, that influence rituximab resistance in B-cell malignancies using genome-wide mapping.

Area of Science:

  • Immunology
  • Genetics
  • Oncology

Background:

  • Therapeutic monoclonal antibodies (mAbs) are vital in treating B-cell malignancies.
  • Understanding mechanisms of mAb resistance is challenging due to limitations in non-human models.

Purpose of the Study:

  • To develop a genetic mapping strategy for identifying genes that influence in vitro drug sensitivity to therapeutic mAbs.
  • To discover novel genes conferring resistance to rituximab, an anti-CD20 MAb.

Main Methods:

  • Genome-wide mapping analyses were employed to identify genetic loci affecting drug sensitivity.
  • Functional validation was performed by knocking down candidate genes in lymphoma cells.

Main Results:

  • Novel genetic loci influencing rituximab responsiveness were discovered.
  • The gene CBLB was identified and functionally validated as conferring rituximab resistance when its expression is reduced in lymphoma cells.

Conclusions:

  • Genome-wide mapping is a powerful approach for discovering novel biological mechanisms of drug resistance.
  • Identifying genes like CBLB can lead to a better understanding of therapeutic monoclonal antibody resistance and potential clinical strategies.

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