Immune Escape of Chronic Myeloid Leukemia in Blast Crisis: The Cross-over of T cell microRNAs, Metabolism and Exhaustion

We observed that T cells from patients with blast crisis (BC) chronic myeloid leukemia (CML) lacked miR-142 and were fewer and exhausted compared with those from patients with chronic phase (CP) CML. Accordingly, the BC Mir142-/-BCR/ABL mouse also presented with T lymphopenia compared with the CP Mir142+/+BCR/ABL mouse. The miR-142 deficit impaired thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into mature T cells and redirected them toward myeloid lineage. The fewer mature T cells that emerged from LMPP differentiation in the BC mouse were enriched with exhausted T effectors. Leukemic blasts-secreted inflammatory cytokines (i.e., IL-6) mediated the miR-142 deficit, which in turn prevented the metabolic reprogramming that allows activated T cells to thrive and expand and promoted expression of the exhaustion marker PD-1. Thus, loss of miR-142 expression ultimately resulted in BC immune escape and disease growth. In fact, immunodeficient mice transplanted with BC CML LSKs and miR-142 KO T cells had shorter survival than those transplanted with BC CML LSKs and miR-142 wild-type T cells. Conversely, BC patient-derived xenograft (PDX) mice receiving autologous T cells and synthetic miR-142 mimic lived longer than those receiving autologous T cells and scramble RNA. Combination of tyrosine kinase inhibitors (TKI) plus synthetic miR-142 and/or PD-1 antibody induced a prolonged survival compared to TKI alone, suggesting that harnessing the host immune system with synthetic miR-142 may provide a novel therapeutic approach for BC CML. Overall design: T cells (2x105/sample) from the spleen of Mir142+/+BCR-ABL (CP CML, n=8 mice) and Mir142-/-BCR-ABL (BC CML, n=6 mice) (BCR-ABL were induced for three weeks by tet-off) mice were sorted, and total RNA was extracted using the miRNeasy Micro Kit (Qiagen, Valencia, CA). RNA sequencing libraries were prepared with Kapa mRNA HyperPrep kit (Kapa Biosystems) according to the manufacturer's protocol. RNA-seq libraries were sequencing on Illumina NovaSeq6000 with the sequencing length of 2x101bp.