Research Overview
Although the genes that drive the development of myeloid blood cancers have largely been defined, there are currently few effective targeted treatment strategies for these diseases, and none that are curative. This illuminates the need to exploit the molecular understanding that has been gained in the last decade through cancer exome sequencing to identify novel therapeutic vulnerabilities in myeloid malignancies. Research in the Elf Lab focuses on dissecting the molecular mechanisms underlying these diseases in order to identifying unique molecular dependencies that can be targeted for therapeutic gain.
MPNs are clonal hematopoietic disorders that arise from a single mutated hematopoietic stem cell and result in the multi-lineage expansion of mature myeloid cells. The classical MPNs comprise three distinct diseases: polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Nearly all MPNs are driven by somatic mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL).All three driver mutations are unified by their shared gain-of-function ability to constitutively activate JAK/STAT signaling. Accordingly, JAK inhibitors remain the only FDA-approved targeted therapy for the treatment of these diseases, and though they impart profound clinical benefit, they lack disease-modifying activity and are not curative.
To address these gaps in knowledge, current areas of interest in the Elf Lab include:
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Dissecting the pathobiology of type 1 versus type 2 CALR mutations in MPNs
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Defining the mechanisms underlying fibrocyte commitment and expansion in MF
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Understanding the role of calcium homeostasis and mitophagy in the control of MPN stem cells and disease progression
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Defining the metabolic landscape of JAK2- and CALR-mutated MPNs
Using molecular, biochemical, and cellular approaches in both in vitro and in vivo models, we aim to use the mechanistic insight we gain from these studies to develop rationally designed therapies that will improve upon existing treatments for these challenging diseases.