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

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