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Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
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Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

Niels Weinhold1, Cody Ashby1, Leo Rasche1

  • 1Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.

Blood
|August 13, 2016
PubMed

Insights

Acquired genetic changes in multiple myeloma drive relapse by promoting cell survival and proliferation. These genetic events, particularly TP53 inactivation, are key to overcoming chemotherapy and enabling clonal evolution.

Area of Science:

  • Oncology
  • Genetics
  • Cancer Biology

Background:

  • Multiple myeloma relapse after chemotherapy poses a significant clinical challenge.
  • Understanding the genetic mechanisms driving treatment resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the genetic alterations underlying relapse in multiple myeloma patients undergoing chemotherapy.
  • To identify key molecular events contributing to treatment resistance and disease recurrence.

Main Methods:

  • Longitudinal study of 33 multiple myeloma patients.
  • Utilized gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing.
  • Analyzed acquired mutations and tumor suppressor gene inactivation, including TP53.

Main Results:

  • Acquired mutations in driver genes and biallelic inactivation of tumor suppressor genes (especially TP53) were identified.
  • These genetic events lead to apoptosis resistance and increased proliferation, driving relapse via clonal evolution.
  • Increased copy number aberrations and tumor suppressor gene inactivation were observed in high-risk patients, indicating genomic instability.

Conclusions:

  • Acquired genetic events significantly enhance the survival and proliferation of myeloma cells.
  • These events promote evolutionary fitness, enabling myeloma cells to survive chemotherapy and cause relapse.
  • Genomic instability is a key feature associated with high-risk multiple myeloma and relapse.

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