Faculty, Staff and Student Publications

Publication Date

10-23-2024

Journal

Blood Cancer Journal

Abstract

The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2-/-γc-/- MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the minimal deleted region (MDR) encoding the DLEU2/miR-15a/miR-16-1 cluster. This model provides an innovative and faster CLL system where monocyte differentiation and macrophage polarization are exacerbated, and T-cells are dysfunctional. MDR deletion inversely correlates with the levels of predicted target proteins including BCL2 and PD1/PD-L1 on murine CLL cells and immune cells. The inverse correlation of miR-15a/miR-16-1 with target proteins has been confirmed on patient-derived immune cells. Forced expression of miR-16-1 interferes with monocyte differentiation into tumor-associated macrophages, indicating that selected ncRNAs drive the protumor phenotype of non-malignant immune cells.

Keywords

MicroRNAs, Leukemia, Lymphocytic, Chronic, B-Cell, Animals, Mice, Tumor Microenvironment, Humans, RNA, Long Noncoding, Tumor Suppressor Proteins, Multigene Family

DOI

10.1038/s41408-024-01142-3

PMID

39438453

PMCID

PMC11496494

PubMedCentral® Posted Date

10-23-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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