The DLEU2/miR-15a/miR-16-1 cluster shapes the immune microenvironment of chronic lymphocytic leukemia
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<sup>-/-</sup>γ<sub>c</sub><sup>-/-</sup> 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.
Authors
- Rolf Swoboda
- Federica Barbaglio (ORCID: https://orcid.org/0000-0001-5528-2197)
- Sarah Schneider
- George A. Călin (ORCID: https://orcid.org/0000-0002-7427-0578)
- Nitin Jain (ORCID: https://orcid.org/0000-0003-0114-8384)
- Varsha Gandhi (ORCID: https://orcid.org/0000-0002-3172-9166)
- Priyanka Khare (ORCID: https://orcid.org/0000-0002-9445-5975)
- Nicholas Chiorazzi (ORCID: https://orcid.org/0000-0003-1023-6650)
- Erika J. Thompson
- Shih‐Shih Chen (ORCID: https://orcid.org/0000-0001-6258-1750)
- V. Behrana Jensen (ORCID: https://orcid.org/0000-0002-8415-8416)
- Recep Bayraktar (ORCID: https://orcid.org/0000-0002-8227-2055)
- Marisela Mendoza
- Cristina Ivan
- Karen Clise-Dwyer (ORCID: https://orcid.org/0000-0001-9954-1197)
- Paolo Ghia (ORCID: https://orcid.org/0000-0003-3750-7342)
- William G. Wierda (ORCID: https://orcid.org/0000-0002-7357-270X)
- Federico Caligaris‐Cappio
- Sashi Kasimsetty
- Maria Teresa Sabrina Bertilaccio (ORCID: https://orcid.org/0000-0002-2304-4618)
- Ronghua Zhang (ORCID: https://orcid.org/0000-0001-8114-4193)
- Xiao‐Jie Yan (ORCID: https://orcid.org/0009-0008-6370-6138)
- Priyanka Banerjee (ORCID: https://orcid.org/0000-0003-1239-7220)
- Michael J. Keating
- Rima Mendonsa
Institutions
- Texas A&M Health Science Center (US)
- Northwell Health (US)
- Feinstein Institute for Medical Research (US)
- The University of Texas MD Anderson Cancer Center (US)
- Vita-Salute San Raffaele University (IT)
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US)
- Italian Association for Cancer Research (IT)
- IRCCS Ospedale San Raffaele (IT)
- Caris Life Sciences (United States) (US)
- Texas A&M University (US)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1038/s41408-024-01142-3
- Citations
- 9
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.94
Funders
- CLL Global Research Foundation
- Ohio State University
- Associazione Italiana per la Ricerca sul Cancro
- Servier
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute