CLL Coverage from Every Angle

Potential Biomarkers in CLL Harboring Trisomy 12 Under Study

By: Julia Fiederlein
Posted: Thursday, May 6, 2021

About one-quarter of patients with chronic lymphocytic leukemia (CLL) harbor trisomy 12 aberrations. Previous studies have suggested that genes located on chromosome 12 may be involved in CLL pathogenesis. Mickie Bhatia, PhD, of McMaster University, Hamilton, Ontario, and colleagues developed a human pluripotent stem cell model with trisomy 12 to identify the targetable features of this chromosomal abnormality. Their preclinical study results were published in Cell Reports.

“This approach offers a plausible basis to screen for targets in the preleukemic state, allowing for early intervention of [patients with monoclonal B-cell lymphocytosis who are] at high clinical risk for leukemic progression,” the investigators commented. “The findings provide immediate translational potential as biomarkers and targets for therapeutic intervention.”

The investigators conducted experiments using heparinized peripheral blood, mononuclear cells, immunodeficient mice, human pluripotent stem cell culture using the CA2 hESC cell line, and several laboratory assessments. These analyses revealed that commonly activated genes in CLL with trisomy 12 might be shared in human pluripotent stem cells harboring the same chromosomal abnormality; thus, human pluripotent stem cells with trisomy 12 could be used for further investigation of putative targets of disease.

The investigators used a chemical screening platform to identify chemical inhibitors of gene targets; in both the CLL- and pluripotent stem cell–based screens, endothelin receptor type B (EDNRB) and interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors were identified as the lead compounds. Drug testing performed on leukemic peripheral blood samples validated EDNRB and IRAK4 as gene targets in CLL with trisomy 12. In patient-derived xenografted mice, an IRAK4 inhibitor demonstrated efficacy in suppressing a target biologically linked to CLL with trisomy 12; treatment with this agent did not seem to impact healthy blood.

Disclosure: The study authors reported no conflicts of interest.

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