Targeting Immune Escape in CML/MPN Transformation

Myeloid neoplasms such as chronic myelogenous leukemia (CML) and myeloproliferative neoplasms (MPN) may over time transform from a chronic phase (CP) into, respectively, blast crisis (BC) or secondary acute myeloid leukemia (sAML). Both of these conditions are poorly responsive to currently available therapies and novel approaches are urgently needed. To this end, we have studied distinct mechanisms of BC/sAML transformation to discover new targets and develop corresponding therapeutic approaches that prevent and cure disease transformation. A common goal of all these studies is to eliminate leukemia stem cells (LSCs) that drive leukemia growth and BC/sAML transformation. In addition to mechanisms of BC/sAML transformation intrinsic to LSCs, we have recently gained insight into those that are extrinsic to LSCs and that involve transformation of the normal bone marrow (BM) microenvironment (or niche) into a “leukemic” one. Herein, we focus on leukemogenic mechanisms that induce T cells' loss of activity and exhaustion and that ultimately drive LSCs' escape from T cells' antileukemic immune surveillance. To this end, microRNAs (miRNAs) are small non-coding RNAs that target messenger RNAs and regulate levels of the corresponding proteins. MIR142, a highly conserved “gene”, encodes miR-142, which is involved in the development and regulation of hematopoiesis and native and adaptive immunity. In humans, MIR142 has been found mutated in lymphoma and AML, but not in CML or MPN. We recently showed that miR-142 downregulation (deficit) occurs in CD34+CD38- LSCs from BC CML patients compared with those from CP CML patients, leading us to postulate its contribution to the evolution of CP-LSCs into BC-LSCs. While investigating these findings in mouse models, we observed that compared with the Mir142+/+BCR-ABL mouse (a CP CML model), the Mir142−/−BCR-ABL mouse (a BC CML model) presented with a profound T cell lymphopenia, and a significant reduction of T cell activity. To this end, we also observed: a. reduced miR-142 level and activity in T cells from BC CML patients compared with those from CP CML patients; b. an association of miR-142 deficit with increased PD-1 expression and T cells' exhaustion; and c. correction of miR-142 deficit with a novel synthetic miR-142 mimic (CpG-M-miR-142), which restored the antileukemic activity of T cells from both human and murine BC/sAML models. Thus, we hypothesize here that miR-142 deficit is acquired by T cells during BC/sAML transformation and contributes to the phenotypic evolution of CML/MPN into BC/sAML via mechanisms that allow LSCs to escape from T cell antileukemic surveillance. To prove our hypothesis, we propose three specific aims (SA): SA#1: To determine the role of the T cells' miR-142 deficit in BC/sAML transformation. SA#2: To dissect the molecular mechanisms through which miR-142 deficit mediates T cells' loss of activity during BC/sAML transformation. SA#3: To target miR-142 deficit in T cells in order to prevent and/or cure BC/sAML transformation. Our ultimate goal is to obtain IND-enabling evidence that CpG-M- miR-142 is a novel targeting therapeutic that restores T cells' immunity, and in turn eliminates BC/sAML LSCs.