Photo of Julie-Aurore Losman,  MD, PhD

Julie-Aurore Losman, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-5146
Fax: (617) 632-4760


JulieAurore_Losman@dfci.harvard.edu

Julie-Aurore Losman, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Assistant Professor, Medicine, Harvard Medical School
  • Assistant Professor, Medical Oncology, Dana-Farber Cancer Institute
  • Associate Physician, Medicine - Hematology, Brigham And Women's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

The goal of my laboratory is to identify vulnerabilities in leukemia cells that can be targeted therapeutically in the hopes of developing novel strategies to treat hematologic malignancies and other cancers. One of the pathways we study is the hypoxia signaling pathway. EglNs (also called PHD) are oxygen-sensitive 2-oxoglutarate-dependent dioxygenases that catalyze the prolyl hydroxylation of the HIFα (hypoxia-inducible factor) subunit of the HIF heterodimer. This targets HIFα for polyubiquitylation and subsequent proteasomal degradation. Inhibition of EglN results in accumulation of HIFα and subsequent activation of hypoxia-inducible gene transcription. We have found that inhibition of EglN inhibits the proliferation of myeloid leukemia cells, suggesting that HIF functions as a myeloid tumor suppressor. This finding has motivated our efforts to determine if inhibitors of the HIF prolyl hydroxylases, which are now in clinical trials for the treatment of anemia, can have therapeutic benefit in myeloid leukemia. Another focus of my laboratory is studying the mechanisms by which Isocitrate Dehydrogenase (IDH) mutants promote cellular transformation. Wild-type IDH enzymes are metabolic enzymes that convert isocitrate to 2-oxoglutarate. Cancer-associated IDH mutants instead produce R-2-hydroxyglutarate (R-2HG), a metabolite that is normally found at very low levels in cells. R-2HG is necessary and sufficient to mediate the transforming effects of mutant IDH. We are currently working to identify the downstream targets of R-2HG that mediate transformation, and working to identify metabolic vulnerabilities that are induce by the presence of this abnormal metabolite in cells.

Publications

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  • Losman JA. Cancer therapy: The leukaemia epigenome targeted. Nature 2017; 543:634-635. PubMed
  • Elf S, Abdelfattah NS, Chen E, Perales-Paton J, Rosen EA, Ko A, Peisker F, Florescu N, Giannini S, Wolach O, Morgan EA, Tothova Z, Losman JA, Schneider RK, Al-Shahrour F, Mullally A. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. 2016. PubMed
  • Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley GS, Root DE, Ebert BL, Kaelin WG. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339:1621-5. PubMed