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Noncoding RNA genes in cancer pathogenesis

Yuri Pekarsky1, Carlo M Croce1

  • 1Department of Cancer Biology and Genetics, The Wexner Medical Center, Columbus, OH, USA.

Advances in Biological Regulation
|January 7, 2019
PubMed

Insights

Researchers found that most chronic lymphocytic leukemia (CLL) cases involve deletions of miR-15a/miR-16-1, leading to BCL2 overexpression and leukemia. This explains CLL sensitivity to venetoclax and ROR1 targeting, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Chronic lymphocytic leukemia (CLL) pathogenesis involves genetic alterations.
  • MicroRNAs (miRNAs) play crucial roles in cancer development.
  • Specific miRNA deletions are implicated in leukemia progression.

Purpose of the Study:

  • To investigate the role of miR-15a and miR-16-1 in CLL.
  • To identify targets of miR-15/16 in leukemia.
  • To explore novel therapeutic strategies for CLL.

Main Methods:

  • Analysis of genetic deletions in CLL patients.
  • Investigating the regulatory relationship between miR-15/16 and BCL2.
  • Identifying other protein targets of miR-15/16 in CLL.
  • Assessing sensitivity to venetoclax and anti-ROR1 antibodies.

Main Results:

  • The majority of CLL cases (75-85%) exhibit deletion of miR-15a and miR-16-1 at 13q14.
  • miR-15/16 are negative regulators of the BCL2 oncogene; their loss leads to BCL2 overexpression.
  • ROR1, an embryonal antigen, is also regulated by miR-15/16 and overexpressed in ~90% of CLL.
  • CLL cells are sensitive to venetoclax and anti-ROR1 antibodies, with synergistic effects observed.

Conclusions:

  • Deletion of miR-15a/miR-16-1 is a key event in CLL pathogenesis, causing BCL2 overexpression.
  • ROR1 is a novel target of miR-15/16 in CLL, presenting a therapeutic target.
  • Combined targeting of BCL2 with venetoclax and ROR1 with monoclonal antibodies shows synergistic efficacy in eliminating CLL cells.
Keywords:
BCL2CLLROR1miR-15/16tRNA derived fragmentstsRNA

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