An identity crisis: the need for core competencies in undergraduate medical education

A medical student perspective on the role of core competencies in undergraduate medical education in light of medical education reform associated with recent Flexner II

JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.Damon Runyon Cancer Research Foundation (DRG-2241-15)Howard Hughes Medical Institute (Faculty Scholars Award)Stand Up To CancerNational Cancer Institute (U.S.) (P50CA165962)National Cancer Institute (U.S.) (P30CA14051)Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) ProgramNational Institutes of Health (U.S.) (grant U54OD020355-01)National Institutes of Health (U.S.) (grant NCI R01CA172636)National Institutes of Health (U.S.) (grant R35CA197594)National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747)

NVP-CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms

Summary Although clinically tested JAK inhibitors offer significant benefit to myeloproliferative neoplasm (MPN) patients, they do not induce molecular remissions. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors which bind the active conformation of JAK2 and enable JAK2 transactivation. We investigated if NVP-CHZ868, a novel type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells and in murine MPN models. JAK2/MPL-mutant cell lines were sensitive to NVP-CHZ868, including type I JAK inhibitor-persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition should be pursued as a therapeutic approach for MPN patients. Significance Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, they cannot significantly reduce the MPN clone. We previously demonstrated that MPN cells can acquire persistence to type I JAK inhibitors, which bind the active conformation of JAK2 and enable activation of JAK2 in trans by other JAK family members. We show that engaging JAK2 in the inactive conformation with the novel type II inhibitor CHZ868 retains efficacy in type I JAK inhibitor persistent cells, and shows increased efficacy in murine models of polycythemia vera and myelofibrosis, including significant reductions in disease burden not observed with first-generation JAK inhibitors. These data demonstrate that type II JAK inhibitors improve the targeting of aberrant JAK2 signaling, offering increased therapeutic efficacy

JAK-STAT Pathway Activation in Malignant and Non-Malignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

The presence of JAK-STAT pathway mutations1-5 in myeloproliferative neoplasm (MPN) patients led to clinical trials of JAK kinase inhibitors, including the JAK1/2 inhibitor ruxolitinib6,7. Ruxolitinib therapy reduces splenomegaly and systemic symptoms in myelofibrosis (MF) and is associated with an improvement in overall survival8-10, however the mechanisms by which JAK inhibitors achieve clinical benefit in MF have not been delineated. MPN patients present with increased levels of circulating pro-inflammatory cytokines, and the increase in systemic cytokines is reversed with JAK inhibitor therapy11,12. We therefore sought to delineate the mechanisms by which JAK inhibitors attenuate cytokine production in MF. Here we show that JAK inhibition inhibits cytokine production in malignant and non-malignant cells. Single cell proteomic profiling demonstrated that hematopoietic cells from MF mice produce a spectrum of inflammatory cytokines. Pan-hematopoietic Stat3 deletion improved survival, reduced disease severity, and reduced cytokine secretion, with efficacy similar to that observed with ruxolitinib therapy. By contrast, restricting loss of Stat3 to the malignant clone did not reduce disease severity or cytokine production in vivo. Consistent with these findings, we found that both malignant and non-malignant cells secrete inflammatory cytokines, and that JAK inhibition reduces cytokine production from both tumor and non-tumor populations. Our results demonstrate that JAK-STAT3 mediated cytokine production from malignant and non-malignant cells contributes to MPN pathogenesis and that inhibition of JAK-STAT signaling in both populations is required for therapeutic efficacy

JAK–STAT Pathway Activation in Malignant and Nonmalignant Cells Contributes to MPN Pathogenesis and Therapeutic Response

The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis (MF) and improves overall survival; however the mechanism by which JAK inhibitors achieve efficacy has not been delineated. MPN patients present with increased levels of circulating pro-inflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single cell profiling demonstrated that hematopoietic cells from MF models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. By contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and non-malignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations