The oncogenic roles of alarmins and monocytes in triple negative myelofibrosis

About This Grant

PROJECT SUMMARY Myelofibrosis (MF) is an aggressive chronic myeloid malignancy characterized by splenomegaly, impaired hematopoiesis, bone marrow (BM) fibrosis, and has a high risk of transforming into acute myeloid leukemia (AML). Recurrent driver mutations in JAK2 pathway genes (i.e., JAK2, CALR, and MPL) are commonly identified in MF patients, and preclinical studies have shown these mutations lead to constitutive activation of the JAK2 pathway, chronic inflammation, and MF development. Accordingly, several JAK2 inhibitors have been approved by the FDA based on their clinical benefit in ameliorating symptoms and improving overall survival (OS) in MF. However, current JAK2 inhibitors are not disease modifying agents and subgroups of MF patients have inferior response to these drugs, particularly triple negative MF (TN-MF) cases that lack JAK2 pathway mutations. Thus, the field is focused on developing new therapeutic strategies to improve clinical outcomes in MF, especially TN- MF. MYC gene is located on chromosome 8 and MYC is a transcription factor that controls the expression of genes involved in metabolism, cell survival and proliferation. Our studies and those of others have shown that MYC plays oncogenic roles in AML and myelodysplastic syndrome (MDS). However, its role in MF pathogenesis is largely unknown. My studies have identified a significant proportion of TN-MF cases have an additional copy of chromosome 8 (trisomy 8) and that MYC expression levels are elevated in hematopoietic stem cells (HSC). Further, modest levels of MYC overexpression in HSC provoked myeloid disease that is akin to MF, and the development of MYC-driven MF requires upregulation of S100a9, an alarmin that plays critical roles in inflammation and innate immunity. Of note, S100a9-mediated inflammatory signals predominantly affect monocytes and macrophages (MΦ) through ALCAM and CD68 receptors, leading to a significant expansion of these cell types. However, genetic deletion and pharmacologic inhibition of S100a9 did not abrogate all MYC- driven MF phenotypes, indicating additional downstream targets of MYC are involved in MF pathogenesis. These findings support the hypotheses that other targets downstream of MYC also contributes to MF and that MYC-directed expansion of monocytes and MΦ contributes to MYC-driven MF. To test these hypotheses, I will assess the contributions of Galectin-3 (Gal-3), an additional alarmin I identified as a MYC downstream target, to MYC-driven MF (Aim 1). In addition, using both genetic and pharmacologic approaches, I will determine the roles of monocytes and MΦ in MYC-driven MF (Aim 2). Collectively, my proposed studies will provide important insights into MYC regulation of alarmin-mediated inflammation while simultaneously addressing unanswered questions in the field of MF biology and therapy.