Programmed necrosis regulation of leukemic transformation.

Veterans Health Administration, Decatur PA

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Abstract

Background and Innovation: Myelodysplastic syndrome (MDS) is a group of bone marrow failure disorders with a high propensity to evolve into acute myelogenous leukemia. Although patients present early with low blood counts (cytopenias). Current therapies target advanced disease; response rates are low and overall survival is poor. One of the strongest risk factors for MDS is advanced age, and a prominent feature of aging is chronic, low-grade inflammation, (inflammaging). In Vanderbilt’s Electronic health record database, we find an association between MDS and both auto-inflammatory disorders as well as pneumococcal pneumonia, sepsis, and latent viral infections such as HSV as EBV (mononucleosis) suggesting the possibility that prior infection or chronic inflammation may potentiate MDS. Thirty percent of MDS patients harbor inactivating mutations in the TET2 gene that are associated with poor outcome. TET2 is a critical epigenetic regulator and is a key factor in downregulating inflammatory responses. Data from mouse models harboring Tet2 inactivation in hematopoietic cells, has established a causative role for inflammation induced by treatment with bacterial products [1] or cytokines [2] [3] in hematopoietic clonal expansion, a hallmark of MDS disease progression. How Tet2 inactivation alters the immune response to common human pathogenic insults such as infection and the impact on hematopoietic stem cell function is not well understood and is critical to devising early intervention strategies. RIPK1(Receptor Interacting Protein kinase ), a pharmacologically targetable serine/threonine kinase, is a critical signaling mediator of inflammation downstream of death receptors as well as the pathogen sensing receptor, TLR4[4]. RIPK1 mediates inflammatory cell death (necroptosis) in hematopoietic stem and progenitor cells[5, 6]. RIPK1 and necroptosis signaling is increased human MDS patient bone marrow samples, most prominent in the erythroid islands [7]. In the setting of TLR4 signaling, RIPK1 binds to the adaptor, TRIF, to activate NFkB and pro-inflammatory gene expression[4]. Data from mouse models demonstrates compromised hematopoietic stem cell function following bacterial infection [8], mediated by direct pathogen sensing by hematopoietic cells through TLR4. RIPK1 is therefore situated at the nexus of critical signaling pathways directing the response of hematopoietic stem cells to pathogens and cytokines. We hypothesize that prior bacterial infection promotes chronic inflammation in the setting of Tet2-deficiency through epigenetic and inflammatory changes that alter innate immune memory, leading to prolonged and inefficient response to subsequent infections, chronic inflammation (inflammaging) to promote clonal expansion and disease progression. Inhibiting by inhibiting RIPK1 kinase function will inhibit the establishment of aberrant innate immune memory, to prevent infection -related chronic inflammation thereby inhibiting clonal expansion and disease progression. Significance to the health of Veterans: MDS is of particular concern in the Veteran population as approximately 46% of Veteran’s are age 65 or older, relative to 15% of the general population [9]. In the Department of Veteran’s Affairs (VA) Midsouth Healthcare Network (VISN9), the estimated incidence of MDS based on an ICD-9 code denoting cytopenias (given for patients with MDS or concern for MDS) is five-fold higher relative to patients of a similar age in the general population (314 vs 23- 65 per 100,000). Currently, the only curative MDS therapy is allogeneic bone marrow transplant inaccessible for the majority of veterans due to co- morbidities and/or lack of a suitable donor. Path to translation/implementation: If successful, this proposal will provide proof of concept studies for establishing RIPK1 as a therapeutic target for early MDS, fulfilling VA-ORD translational pipeline stage T0-2 and consistent with VA research strategic priority #2, to increase the substantial real-world impact of VA research.