TY - JOUR
T1 - The DLEU2/miR-15a/miR-16-1 cluster shapes the immune microenvironment of chronic lymphocytic leukemia
AU - Zhang, Ronghua
AU - Khare, Priyanka
AU - Banerjee, Priyanka
AU - Ivan, Cristina
AU - Schneider, Sarah
AU - Barbaglio, Federica
AU - Clise-Dwyer, Karen
AU - Jensen, Vanessa Behrana
AU - Thompson, Erika
AU - Mendoza, Marisela
AU - Chiorazzi, Nicholas
AU - Chen, Shih Shih
AU - Yan, Xiao Jie Joy
AU - Jain, Nitin
AU - Ghia, Paolo
AU - Caligaris-Cappio, Federico
AU - Mendonsa, Rima
AU - Kasimsetty, Sashi
AU - Swoboda, Ryan
AU - Bayraktar, Recep
AU - Wierda, William
AU - Gandhi, Varsha
AU - Calin, George A.
AU - Keating, Michael J.
AU - Bertilaccio, Maria Teresa Sabrina
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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. (Figure presented.).
AB - 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. (Figure presented.).
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U2 - 10.1038/s41408-024-01142-3
DO - 10.1038/s41408-024-01142-3
M3 - Article
C2 - 39438453
AN - SCOPUS:85207182688
SN - 2044-5385
VL - 14
JO - Blood cancer journal
JF - Blood cancer journal
IS - 1
M1 - 168
ER -