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Genomic Landscape of CLL: Research Sheds Light on Molecular Subgroups and Targets

By: Vanessa A. Carter, BS
Posted: Wednesday, November 24, 2021

Daniel Mertens, PhD, of the German Cancer Research Center (DKFZ), Heidelberg, and colleagues aimed to identify biologic subgroups of chronic lymphocytic leukemia (CLL), as well as the cooperating pathogenic mechanisms that may facilitate microenvironmental interaction or distinct pathways amid disease evolution and development. Published in Nature Communications, their results offer a basis for understanding the pathogenesis and pathway dependencies of CLL and determined molecular targets that may influence further research.

“Compound combinations targeting, for example, BCL2 and PRMT5 or XPO1, together with anti-CD20 monoclonal antibodies, may specifically synergize in genomically unstable cases,” the study authors concluded. “Future assessment of the subtype-related outcome in comprehensively characterized trial cohorts testing BCL2, BTK, and other inhibitors in development will further elucidate the therapeutic potential of such treatment combinations.”

Specimens were obtained from patients with CLL who experienced disease progression from the REACH1 and CLL8 trials. Samples were CD19 sorted or unsorted, and RNA and DNA were purified and analyzed for integrity. Experimental platforms such as whole-exome sequencing, single-nucleotide polymorphism array analysis, Human Exon 1.0 ST arrays, reduced representation bisulfite sequencing, and Western blot were performed.

Ultimately, CLL can be characterized by two different subtypes—either genomic instability or epithelial-mesenchymal-transition (EMT)-like programs—that are further subdivided into inflammatory and non-inflammatory subgroups. CLL with genomic instability may interfere with DNA-damage response and may disrupt the integrity of the genome, often correlating with mutagenesis. Notably, TP53 wild-type and aberration cases have had poor progression-free survival upon relapse. In contrast, EMT-like CLL tends to display high genomic stability; EMT-like differentiation is inhibited by DNA damage, and there is a reduced benefit when rituximab is added to treatment.

Disclosure: For full disclosures of the study authors, visit nature.com.



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