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3152 Acquired microRNA-142 Deficit Drives Escape Mechanisms of Anti-Leukemic Surveillance during Blast Crisis Transformation of Chronic Myeloid Leukemia (CML)

Program: Oral and Poster Abstracts
Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Non-Biological therapies, Translational Research, CML, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Fang Chen1*, Dandan Zhao1, Yi Zhang1,2*, Yongfang Xu1*, Min-Hsuan Chen3*, Khyatiben V. Pathak4,5*, Yong Liang6*, Wei-Le Wang7*, Katrina Estrella1*, Xiwei Wu, PhD, MD3*, Lucy Y. Ghoda, PhD1*, Ya-Huei Kuo, PhD1, Haris Ali, MD1, Jianhua Yu, PhD8, Michael A Caligiuri, MD9, Mark Boldin7*, Piotr Swiderski6*, Marcin Kortylewski, PhD10*, Patrick Pirrotte4,5*, Le Xuan Truong Nguyen, PhD1,4*, Guido Marcucci, MD1 and Bin Zhang1*

1Department of Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA
2Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
3City of Hope National Medical Center, Integrative Genomics Core, Department of Computational and Quantitative Medicine, Beckman Research Institute, Duarte, CA
4Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ
5Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA
6DNA/RNA Peptide Shared Resources, Beckman Research Institute, Duarte, CA
7Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA
8Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
9Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA
10Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA

CML may evolve from a chronic phase (CP) into blast crisis (BC), but the underlying mechanisms of the transformation remain to be fully elucidated. We reported that microRNA (miR)-142 is downregulated in BC compared with CP patients; and in a murine model of CP CML (i.e., BCR-ABL mouse), miR-142 knock-out (KO) induced a BC-like phenotype, substantiating a mechanistic role of miR-142 deficit in BC transformation. Mechanistically, miR-142 KO induced mitochondrial fusion and increased oxidative phosphorylation (OxPhos) in leukemic stem cells (LSCs), causing a shift of leukemic phenotype from CP to BC (Nat Commun, in press). Herein, we report that miR-142 deficit also occurs in T lymphocytes of BC patients due to inflammatory cytokines that are aberrantly produced by the proliferating leukemic cells. Using the Mir142−/−BCR-ABL mouse, we observed that miR-142 deficit resulted in loss of T cell number and activity, suppressed the antileukemic immune surveillance, and contributed to BC transformation. In fact, miR-142 KO hampered thymic lymphoid-primed multipotent progenitor (LMPP) differentiation into T cells and rendered mature T cells dysfunctional and exhausted, with increase of PD-1 levels, and decrease of the apoptotic threshold, cell cycling and cytokine production, via blockade of OxPhos/glycolysis switch that regulates the metabolism of otherwise activated T cells. These changes translated into a decrease of T-cell antileukemic surveillance as demonstrated by increased numbers of BC murine Lin-Sca-1+c-Kit+ (LSKs) or human CD34+ blasts cocultured with Mir142−/− T-cells vs those cocultured with Mir142+/+ T-cells. Furthermore, congenic B6 (lethally irradiated to eradicate host T cells) or immunodeficient NSG (no T cells) recipient mice transplanted with Mir142−/−BCR-ABL LSK and Mir142−/− T cells had reduced T cells (both: p<0.0001), increased blasts (B6: p=0.01; NSG: p<0.0001) and a shorter survival (median survival for B6: 58 days vs unreached, p=0.008; for NSG: 28 days vs unreached, p<0.0001) compared with the respective controls transplanted with Mir142−/−BCR-ABL LSK and Mir142+/+ T cells. Transplantation of Mir142−/−BCR-ABL LSKs into Mir142−/− or Mir142flox(f)/fLck-cre+ (i.e., miR-142 KO only in T cells; Mir142TΔ/Δ) recipients also resulted in a shorter survival than Mir142+/+ recipients (median survival for Mir142−/− vs Mir142+/+ recipients: 44 vs 53 days, p=0.001; for Mir142TΔ/Δ vs Mir142+/+ recipients: 42 vs 53 days, p=0.0002).

To correct miR-142 deficit, we produced a synthetic miR-142 mimic oligonucleotide (CpG-M-miR-142). We treated a cohort of NSG mice transplanted with Mir142−/−BCR-ABL LSKs and Mir142−/− T cells, with CpG-M-miR-142 (30mg/kg/day, IV) or CpG-scramble RNA (SCR) for 3 weeks. We observed increased T cells (p=0.04), decreased blasts (p=0.0029) and longer survival (median survival: unreached vs 37 days, p=0.0005) in CpG-M-miR-142-treated recipients vs SCR-treated controls. Similar results were observed in CpG-M-miR-142-treated Mir142−/−BCR-ABL mice vs SCR-treated controls. To test CpG-M-miR-142 activity in human T cells, a cohort of BC CML patient-derived xenograft (PDX) mice were given patient’s autologous T cells and CpG-M-miR-142. Mice receiving T+CpG-M-miR-142 had increased T cell expansion (p=0.04), reduced leukemic cells (p=0.0078), and longer survival (median survival: 53 vs 38 days, p=0.01) than controls receiving T+SCR. In secondary transplants, the recipients of BM from T+CpG-M-miR-142-treated donors survived longer (median survival: 73 vs 53 days, p<0.0001) than the recipients of BM from T+SCR-treated donors, suggesting a decrease in LSC burden.

Finally, we tested the efficacy of tyrosine kinase inhibitors (TKIs), which represent the primary targeting approach for CML, in combination with CpG-M-miR-142 and/or PD-1 inhibitor in Mir142−/−BCR-ABL mice. The mice treated with TKI+CpG-M-miR-142 (median survival: 107 days, p=0.001) or TKI+PD-1 inhibitor (104 days, p=0.002) survived longer than the controls treated with TKI alone (66 days); the triplet combination (TKI+CpG-M-miR-142+PD-1 inhibitor) is expected to improve survival further (ongoing experiment).

In summary, CpG-M-miR-142 alone and in combination with TKI or PD-1 inhibitor rescued T-cell antileukemic activity and prolonged survival in BC CML murine and PDX models, thereby providing a potentially new therapeutic approach for BC CML.

Disclosures: Ali: Karyopharm: Consultancy; GSK: Consultancy; Pharmaessentia: Consultancy; Blueprints: Speakers Bureau; BMS: Speakers Bureau; Incyte: Research Funding. Nguyen: Ostentus Therapeutics: Current equity holder in private company. Marcucci: Ostentus Therapeutics: Current equity holder in private company, Research Funding.

*signifies non-member of ASH