Fleischman, Angela - University of California, Irvine - Department of Biological Chemistry

研究领域

Research Abstract My overarching research goal is to identify what drives disease initiation in myeloproliferative neoplasm (MPN), a chronic leukemia, and to use this knowledge to develop therapies to treat or prevent this disease. MPN is characterized by the somatic acquisition of a mutation in either JAK2 (JAK2V617F) or calreticulin in a hematopoietic stem cell. This mutant clone expands producing excessive numbers of mature myeloid cells. The clinical consequences of MPN are elevated peripheral blood counts, thrombosis, splenomegaly, debilitating constitutional symptoms, excessive inflammation, and transformation to acute leukemia. There is a critical need for novel therapeutic targets in MPN. Bone marrow transplantation is the only therapy that alters the natural history of the disease but the majority of patients with MPN are not candidates for this procedure due to age and comorbidities. JAK inhibitors are currently in development, but the impact of JAK as a target in MPN has been disappointing. Understanding the fundamental mechanisms by which the neoplastic clone is first established in MPN patients is necessary to develop therapeutics with curative intent. We have developed a model in MPN whereby inflammatory insult upon a vulnerable hematopoietic stem cell pool drives the emergence of clones which have mutated in such a way to avoid these suppressive and/or apoptotic cues. This model is based on our findings that the JAK2 mutation endows resistance to the inflammatory cytokine TNF-alpha. The recent identification of calreticulin mutations in most MPN patients without JAK2V617F aligns nicely with my model. Calreticulin is an “eat me” signal on stressed cells allowing for their “clean and quick” phagocytosis by macrophages. MPN represents an excellent model disease in which to study the fundamental mechanisms of leukemogenesis because of its defined genetic lesions, chronic nature of the disease, and the ability to quantitatively measure the neoplastic clone over time. We hope that our work will not only lead to direct benefit for MPN patients, but will also lead to new therapies for other hematologic malignancies.

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Fleischman AG, Tyner JW. Causal role for JAK2V617F in thrombosis. Blood, 2013 Nov 28;122(23):3705-6. PMID: 24288407 Fleischman AG, Maxson JE, Luty SB, Agarwal A, Royer LR, Abel ML, Macmaniman JD, Loriaux MM, Druker BJ, Tyner JW. The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood, 2013 Nov 21;122(22):3628-31. PMID: 24081659 Fleischman AG, Maziarz RT. Hematopoietic Stem Cell Transplantation for Myelofibrosis: Where Are We Now? Current Opinion Hematology, 2013 Vol. 20(2):130-6. PMID: 23314844 Sanda T, Tyner JW, Gutierrez A, Ngo VN, Glover JM, Chang BH, Yost A, Ma W, Fleischman AG, Zhou W, Yang Y, Kleppe M, Ahn Y, Tatarek J, Kelliher MA, Neuber DS, Levine RL, Moriggl R, Müller M, Gray NS, Jamieson CHM, Weng AP, Staudt LM, Druker BJ, Look AT. TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia. Cancer Discovery, 2013 Vol. 3(5):564-577. PMID: 23471820 Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Eide CA, Bottomly D, Wilmot B, McWeeney SK, Tognon CE, Pond JB, Collins RH, Deininger MW, Chang BH, Loriaux MM, Druker BJ, Tyner JW. Targetable CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML. New England Journal of Medicine, 2012 Vol. 368(19):1781-90. PMID: 23656643 Fleischman AG*, Agarwal A*, Petersen CL*, Mackenzie R, Luty SL, Loriaux M, Druker BJ, Woltjer RL, Deininger MW. *authors have equal contribution. Effects of Plerixafor in combination with tyrosine kinase inhibition in a murine model of CML. Blood, 2012 Vol 120(13):2658-68. PMID: 22889761 Fleischman AG, Tyner, JW. JAK2V617F down-modulates MPL. Blood, 2012 Vol. 119(20):4579-80. PMID: 22596167 Fleischman, AG. ALDH Marks Leukemic Stem Cells. Blood, 2012 Vol 119(15):3376-7. PMID: 21860020 Fleischman AG, Aichberger KJ, Luty SL, Bumm TG, Petersen CL, Dorototaj S, Vasudevan KB, LaTocha DH, Yang F, Press RD, Loriaux MM Pahl H, Silver RT, Druker BJ, Bagby GC, Deininger MW. Role of Tumor Necrosis Factor-alpha in clonal evolution of JAK V617F positive myeloproliferative neoplasm. Blood, 2011 Vol 118 (24):6392-6398. PMID: 21860020 Bagby GC and Fleischman AG. The stem cell fitness landscape and pathways of molecular leukemogenesis. Front Biosci (Schol Ed), 2011 Jan 1;3:487-500. PMID: 21196392 Aichberger KJ, Fleischman AG, Deininger MW. Same mutation, different allele. Blood, 2009 Vol. 114(14), 3018-3023. PMID: 19797527 Hsu C-L*, King-Fleischman AG*, Lai AY, Matsumoto,Y, Weissman IL, Kondo M. *Authors contributed equally to this work. Antagonisitic action of C/EBPa and Pax5 in myeloid or lymphoid lineage choices in common lymphoid progenitors. PNAS, 2006 Vol 103, 672-677. PMID: 16407117