Abstract 1694: CHIP and AML mutations dictate the composition of hematopoietic microenvironments

Abstract

Abstract Clonal Hematopoiesis of Indeterminate Potential (CHIP) is the age-associated acquisition of detectable stem cell mutations, known to predispose patients towards Acute Myeloid Leukemia (AML) and cardiovascular disease. While progression to AML is believed arise from the acquisition of additional clonal mutations, cardiovascular disease is thought to be a consequence of aberrant pro-inflammatory signaling[1]. Here, we show that the development of genetic aberrations seen in CHIP disorders can profoundly shift the cellular composition of multiple hematopoietic microenvironments. TP53 is the most frequently mutated gene in human cancers and is one of several frequently mutated genes in CHIP and AML[2]. To model loss of Trp53 in a subset of cells of the hematopoietic system, we generated mixed bone marrow chimeras by transplantation of either Trp53−/− or wild type bone marrow mononuclear cells (BMNCs) in conjunction with congenic wild type cells. Following reconstitution, we observed increased levels of wild type T cells in mice transplanted with Trp53−/− BMNCs. Interestingly, both CD4+ and CD8+ T cells showed increases in naïve T cell subsets while only CD4+ T cells showed an increase in effector/effector memory T cell subsets. In line with these results, we observed a short-term decrease in the number of effector/effector memory T cells in the wild type compartment of Trp53−/− chimeras, indicating delayed effector T cell formation. To determine if these alterations were mirrored in the leukemic setting, we next generated MLL-AF9 and Trp53−/−;NrasG12D leukemia, faithfully modeling the intrapatient heterogeneity which occurs as a result of CHIP progressing to AML [2] by transplanting both Trp53−/− and Trp53−/−;NrasG12D KSL into sublethally irradiated primary recipients. While the bone marrow of Trp53−/−;NrasG12D leukemia showed the presence of both invading T and B lymphocytes, MLL-AF9 showed a near complete absence of lymphocytes, reminiscent of ‘immune-infiltrated' and ‘immune-desert' phenotypes seen in solid tumors. These data clearly demonstrate a cell-extrinsic effect of partial Trp53 loss in the hematopoietic system in the absence of a leukemic clone, which could potentially serve to explain the paradoxical observation that immunoediting does not occur in a mouse model of MLL-ENL[3]. Thus, CHIP may constitute a novel and leukemia-specific means of immunoediting via diverse alteration of the hematopoietic microenvironment prior to the development of malignancy. 1. Jaiswal, S., et al., Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. New England Journal of Medicine, 2017. 377(2): p. 111-121. 2. Steensma, D.P., et al., Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood, 2015. 126(1): p. 9-16. 3. Dudenhöffer-Pfeifer, M. and D. Bryder, Immunoediting is not a primary transformation event in a murine model of MLL-ENL AML. Life Science Alliance, 2018. 1(4): p. e201800079. Citation Format: Ryan R. Posey, Lourdes M. Mendez, Jonathan D. Lee, John G. Clohessy, Pier Paolo Pandolfi. CHIP and AML mutations dictate the composition of hematopoietic microenvironments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1694.