Project Grant R01CA280116

MYC-ALARMIN AXIS AS A NOVEL THERAPEUTIC VULNERABILITY IN MYELOFIBROSIS - PROJECT SUMMARY MYELOFIBROSIS (MF) IS A HEMATOLOGIC MALIGNANCY THAT IS CHARACTERIZED BY CONSTITUTIONAL SYMPTOMS, SPLENOMEGALY, BONE MARROW (BM) FIBROSIS, AND HIGH RISK OF TRANSFORMATION TO ACUTE MYELOID LEUKEMIA (AML). MF IS AMONG THE MOST AGGRESSIVE CHRONIC MYELOID NEOPLASMS, WITH A MEDIAN OVERALL SURVIVAL (OS) LESS THAN 4 YEARS. SOMATIC MUTATIONS IN THE JAK2, CALR, AND MPL GENES ARE COMMON IN ~85% OF MF PATIENTS, AND PRECLINICAL STUDIES HAVE SHOWN THAT THESE MUTATIONS RESULT IN CONSTITUTIVE ACTIVATION OF THE JAK/STAT PATHWAY, LEADING TO CHRONIC INFLAMMATION AND BM FIBROSIS. ACCORDINGLY, THE FDA HAS APPROVED THREE JAK2 INHIBITORS, RUXOLITINIB, FEDRATINIB, AND PACRITINIB, BASED ON THEIR CLINICAL IMPROVEMENTS IN CONSTITUTIONAL SYMPTOMS, SPLENOMEGALY AND OS. HOWEVER, A SUBSTANTIAL FRACTION OF MF PATIENTS LACK JAK2-ACTIVATING MUTATIONS. MOREOVER, JAK2-ACTIVATING MUTATIONS PERSIST IN PATIENTS UNDERGOING JAK2 INHIBITOR THERAPIES AND A SUBGROUP OF PATIENTS HAVE SUBOPTIMAL RESPONSE TO JAK2 INHIBITORS, UNDERSCORING THE URGENT NEED FOR DEVELOPING NEW THERAPEUTIC STRATEGIES TO IMPROVE CLINICAL OUTCOMES. MYC IS A TRANSCRIPTION FACTOR THAT CONTROLS CELL PROLIFERATION, SURVIVAL, AND METABOLISM. ALTHOUGH MYC PLAYS IMPORTANT ONCOGENIC ROLES IN MYELOID MALIGNANCIES SUCH AS AML, ITS ROLE IN THE MF PATHOGENESIS IS UNKNOWN. NOTABLY, OUR RECENT STUDIES REVEALED THAT MYC COPY NUMBER GAIN FREQUENTLY OCCURS IN MF PATIENTS AND THAT THIS IS ASSOCIATED WITH INCREASED LEVELS OF MYC PROTEIN EXPRESSION IN PATIENT BM CELLS. IMPORTANTLY, WE HAVE SHOWN THAT ACTIVATION OF MYC EXPRESSION IN MOUSE HEMATOPOIETIC STEM CELLS (HSCS) IS SUFFICIENT TO PROVOKE MF INDEPENDENT OF JAK2, CALR, AND MPL MUTATIONS, AND THAT THIS REQUIRES UPREGULATION OF S100A9, AN ALARMIN OR DANGER ASSOCIATED MOLECULAR PATTERNS (DAMPS) PROTEIN THAT PLAYS PIVOTAL ROLES IN INFLAMMATION AND INNATE IMMUNITY. ACCORDINGLY, THE MYC-S100A9 AXIS UNDERLIES COMPLEX NETWORK OF INFLAMMATORY SIGNALING THAT INVOLVES VARIOUS HEMATOPOIETIC CELL TYPES IN THE BM NICHE. FINALLY, WE DISCOVERED THAT MYC ALSO INDUCES EXPANSION OF MESENCHYMAL STROMAL CELLS (MSCS) THAT ARE KNOWN AS MYOFIBROBLASTS CONTRIBUTING TO THE MF PATHOGENESIS. THESE FINDINGS SUPPORT THE HYPOTHESES THAT ACTIVATION OF MYC-ALARMIN PATHWAY DRIVES MF INDEPENDENT OF JAK2/CALR/MPL MUTATIONS AND THAT INHIBITING MYC OR ITS TARGET ALARMINS WILL IMPROVE CLINICAL OUTCOMES IN MF PATIENTS HAVING INCREASED MYC EXPRESSION. TO TEST THESE HYPOTHESES, WE WILL ASSESS THE PRECLINICAL ACTIVITY OF PHARMACOLOGIC AGENTS TARGETING THE MYC-S100A9 AXIS IN MF AND DETERMINE THE MECHANISMS OF MYC-DIRECTED UPREGULATION OF S100A9 (AIM 1). FURTHER, WE WILL ASSESS THE ROLES OF MYC-S100A9 CIRCUIT IN ACTIVATION AND EXPANSION OF MYOFIBROBLASTS AND THEIR CONTRIBUTION TO MF DEVELOPMENT (AIM 2). FINALLY, WE WILL DEFINE THE ROLES OF MYC AND ITS TARGET ALARMINS IN MF DRIVEN BY JAK2 PATHWAY MUTATIONS (AIM 3). COLLECTIVELY, THIS RESEARCH WILL PROVIDE IMPORTANT INSIGHTS INTO A NEW MOLECULAR CIRCUIT CONNECTING MYC AND ALARMIN-MEDIATED INFLAMMATION, AND WILL TEST IF THE MYC-ALARMIN AXIS REPRESENTS A NOVEL THERAPEUTIC VULNERABILITY THAT CAN BE TARGETED TO IMPROVE CLINICAL OUTCOMES IN MF.