Despite the growing knowledge on genetic mutations that drive myeloproliferative neoplasms (MPN), effectors downstream of genetic driver activity contributing to disease progression and disease associated complications remain largely unknown. We previously demonstrated that mice expressing MPN driver mutations including JAK2-V617F in hematopoietic system developed not only expected MPN disease associated hematopoietic phenotypes, but also displayed hematopoietic cell intrinsic and systemic metabolic changes that contributed to MPN progression.

Metabolomics, cytokine arrays and ELISA based analyses were conducted on plasma and bone marrow samples isolated from MPN mouse models and patients to identify factors downstream of genetic drivers promoting MPN progression. Receiver operating curve analysis was performed to assess the sensitivity and specificity of GDF15 for predicting MPN progression in patients. Chromatin immunoprecipitation and immunoblotting was conducted to identify upstream transcriptional regulators of GDF15 expression in MPN cells. Genetic inhibition and pharmacological modulation of GDF15 was performed to assess its relevance in MPN pathogenesis.

We uncovered that expression of MPN driver mutations including mutant JAK2 and CALR-del52 in mice and in human leukemic cell lines leads to elevated levels of growth differentiation factor 15 (GDF15), which was correlated with MPN progression and disease associated systemic metabolic changes including hypoglycemia and body weight reduction. Patients with MPN also showed increased GDF15 levels, with the highest levels found in myelofibrotic (MF) patients. GDF15 levels correlated with mutant allele burden and showed sensitivity and specificity to distinguish MPN patients from healthy controls. At the molecular level, we identified that JAK-STAT signaling induces GDF15 expression through the activation of early growth response 1 (EGR1). Exogenous supplementation of GDF15 promoted murine and human hematopoietic colony growth in vitro and augmented MPN progression in mutant JAK2 mice. Conversely, pharmacological inhibition of GDF15 with a functional neutralizing anti-GDF15 antibody reduced MPN cell growth in humanized mice.

Our findings identify GDF15 as a critical inducer of disease progression and systemic metabolic changes in MPN and highlight it as a diagnostic and therapeutic target in MPN.