BBS Faculty Member - Ann Mullally

Ann Mullally, MD

Department of Medicine, HMS
Division of Hematology and Medicine, Brigham and Women's Hospital

Brigham and Women's Hospital
75 Francis Street
Boston, MA 02115
Tel: 617-525-4955
Fax: 617-525-4986
Email: amullally@partners.org
Visit my lab page here.



The Mullally laboratory is a translational oncology lab focused on the study of myeloid blood cancers, primarily myeloproliferative neoplasms (MPN). We employ a range of experimental approaches including murine models, functional genomics and proteomics as well as cellular and molecular biology.

The Mullally lab recently elucidated the mechanism by which mutant calreticulin (CALR), an endoplasmic reticulum chaperone protein, is oncogenic and causes MPN. We found that the thrombopoietin receptor, MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation. We further demonstrated that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the tumor-specific C-terminus of the mutant protein and that mutant CALR physically interacts with MPL. Current studies in the lab are focused on understanding how mutant CALR activates MPL signaling to induce MPN and determining the differential binding interactions and signaling targets of mutant CALR. We are also interested in mutant CALR as an immunotherapeutic target. Although more than thirty
CALR mutations have been identified, all result in the generation of a common, 36-amino acid novel C-terminal CALR peptide, representing a tumor-specific neo-antigen that we plan to target for more effective, less toxic immunotherapy of MPN.

The lab has extensive expertise with genetic murine models and hematopoietic stem cell (HSC) biology. We established a murine model of the JAK2V617F mutation, the most common molecular abnormality in MPN and have used this as a pre-clinical model to investigate the effects of interferon therapy on MPN stem cells. More recently, we identified the DNA helicase, RECQL5 as a critical regulator of genome stability in MPN and demonstrated that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F-mutant cells through RECQL5-targeted synthetic lethality.

The lab is also studying the genetic events (e.g. TET2 loss) that drive the transformation of MPN to acute myeloid leukemia (AML) with the goal of developing improved treatments for these leukemias, which are highly chemo-refractory. Other projects are focused on advancing the understanding of the biology of myelofibrosis, an aggressive subtype of MPN and on investigating the differential molecular dependencies and bone marrow niche interactions of MPN disease-propagating stem cells.



Last Update: 7/7/2017



Publications

For a complete listing of publications click here.

 


 

Elf, S, Abdelfattah, N, Chen, E, Perales-Patón, 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 to transform hematopoietic cells. Cancer Discovery 2016 Apr;6(4):368-81.

Chen, E, Ahn, JS, Sykes, DB, Breyfogle LJ, Godfrey AL, Nangalia, J, Ko, A, Deangelo, DJ, Green, AR,
Mullally A. RECQL5 suppresses JAK2V617F-induced replication stress and genomic instability. Cell Reports 2015 Dec 22;13(11):2345-52.

Chen, E, Schneider, RK, Breyfogle, LJ, Rosen, E, Poveromo, L, Elf, S, Ko, A, Brumme, K, Levine, R, Ebert, BL,
Mullally, A. Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice combine to promote disease progression in myeloproliferative neoplasms. Blood 2015 Jan 8;125(2):327-35.

Mullally, A*, Bruedigam, C, Poveromo, L, Heidel, FH, Purdon, A, Vu, T, Austin, R, Heckl, D, Breyfogle, LJ, Paine Kuhn, C, Kalaitzidis, D, Armstrong, SA, Williams, DA, Hill, GR, Ebert, BL, Lane SW*. Depletion of Jak2V617F MPN-propagating stem cells by interferon-alpha in a murine model of polycythemia vera. Blood 2013 May 2;121(18): 3692-702. (*co-corresponding authors)



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