Faculty Profile

Dr. Britta Will, Ph.D.

Britta Will, Ph.D.

Assistant Professor, Department of Medicine (Oncology)

Assistant Professor, Department of Cell Biology

Areas of Research: Hematopoietic Stem Cells (HSC), Regulation of Stem Cell Fate, Myelodysplastic Syndrome and Acute Myeloid Leukemia, Mouse Models of Leukemogenesis, Testing of novel stem cell-directed therapeutics on primary human HSCs.

Professional Interests

Mechanisms of stem cell aging and transformation

Hematopoietic stem cells (HSC) maintain multi-lineage blood formation throughout our lifetime. Balancing stem cell regeneration and differentiation commitment to produce mature blood cells is quintessential for a healthy hematopoietic system. Dysregulation of such HSC fate determination processes can lead to loss of immune function, bone marrow failure, and malignant transformation during aging. However, up to date very little is known about the molecular events driving age-related HSC changes and how they contribute to disease. Understanding age-associated molecular alterations will not only uncover fundamental mechanisms guiding function of HSCs, but may also allow for therapeutic intervention to “rejuvenate” aged hematopoietic systems and possibly even prevent age-associated hematopoietic diseases. Our mission is to clarify the central mechanisms establishing and guarding sustained hematopoietic stem cell function, particular those that drive leukemogenesis, if disrupted.  We develop innovative genetic mouse models, use ex vivo and in vivo primary mouse and human stem cell assay systems, exploit lentiviral gene transfer, and apply state-of-the-art molecular biology and next generation sequencing techniques. Currently, we have four major project lines in the laboratory:

The labile iron pool as a rheostat for stem cell function. Our recent work has uncovered a key role of the amount of readily accessible intracellular iron (termed labile iron pool, LIP) in instructing HSC self-renewal (Kao et al., STM 2018). We are currently investigating the precise molecular mechanism of action, particularly focusing on metabolic and non-enzymatic molecular pathways relying on iron – a completely uncharted territory for healthy as well as leukemic stem cells.  

Gene expression program erosion in aging stem cells and leukemia. Our past work has demonstrated a causative role of even minimal dosage alterations of a key transcription factor instructing hematopoiesis, PU.1, for myeloid leukemia evolution (Will et al., Nat Med 2015). Current efforts research focus on understanding (1) how such slight deviations from optimal PU.1 dosage lead to the erosion of PU.1-dependent gene expression programs, and (2) in which way a slightly altered PU.1 gene expression network can functionally cooperate with age-associated inactivation of epigenetic regulators (TET2 and DNMT3A).

Molecular safeguards in cancer stem cells. Teamed-up with Dr. Ana Maria Cuervo (Dept. of Developmental & Molecular Biology), the discoverer of a highly precise protein degradation pathway named chaperone-mediated autophagy, we are investigating the role of this stress-related molecular defense mechanism in leukemic stem cell evolution and maintenance.

Improving stem cell-directed therapies. We are actively engaging with commercial research partners to test and evaluate novel therapeutic options for patients with hematologic malignancies. We have uncovered a beneficial role of eltrombopag, a small molecule thrombopoietin receptor mimetic and iron chelator, for enhancing platelet production (Will et al., Blood 2009) as well as healthy HSC function (Kao et al., STM 2018). Our current work looks into how eltrombopag can be efficiently combined with standard-of-care treatment regimen for patients suffering from treatment or disease-initiated thrombocytopenia.

Selected Publications

Full list of publications at: https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/47490382/?sort=date&direction=descending

Kao YR, Chen J, Narayanagari SR, Todorova TI, Aivalioti M, Ferreira M, Ramos-Marques P, Pallaud C, Mantzaris I, Shastri A, Bussel JB, Verma A, Steidl U*, Will B*. Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag. Science Translational Medicine 12 Sep 2018: Vol. 10, Issue 458, eaas9563 DOI: 10.1126/scitranslmed.aas9563 [* co-corresponding authors]

Shastri A*, Choudhary GS, Ferreira-Teixeira M, Gordon-Mitchell S, Ramachandra N, Benard L, Bhattacharyya S, Lopez R, Pradhan K, Giricz O, Ravipati G, Wong L, Cole SL, Bhagat T, Feld J, Dhar J, Bartenstein M, Thiruthuvanathan VJ, Wickrema A, Ye H, Frank DA, Pellagatti A, Boultwood J, Zhou T, Kim Y, MacLeod AR, Epling-Burnette P, Ye M, McCoon P, Woessner R, Steidl U, Will B*, Verma A*. Antisense inhibition of STAT3 as a therapeutic strategy against MDS and AML stem cells. JCI 2018; (in press). [* co-corresponding authors]

Will B*, Vogler TO, Narayanagari S, Bartholdy B, Todorova TI, da Silva Ferreira M, Chen J, Yu Y, Mayer J, Barreyro L, Carvajal L, Neriah DB, Roth M, van Oers J, Schaetzlein S, McMahon C, Edelmann W, Verma A, Steidl U*. Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat Med. 2015 Oct;21(10):1172-81. PubMed PMID: 26343801. [* co-corresponding authors]

Will B, Vogler TO, Bartholdy B, Garrett-Bakelman F, Mayer J, Barreyro L, Pandolfi A, Todorova TI, Okoye-Okafor UC, Stanley RF, Bhagat TD, Verma A, Figueroa ME, Melnick A, Roth M, Steidl U. Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment. Nat Immunol. 2013 May;14(5):437-45. PubMed PMID: 23563689; PubMed Central PMCID: PMC3633104.

Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C, Tamari R, Yu Y, Bhagat TD, Bhattacharyya S, Barreyro L, Heuck C, Mo Y, Parekh S, McMahon C, Pellagatti A, Boultwood J, Montagna C, Silverman L, Maciejewski J, Greally JM, Ye BH, List AF, Steidl C, Steidl U, Verma A. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood. 2012 Sep 6;120(10):2076-86. PubMed PMID: 22753872; PubMed Central PMCID: PMC3437595.

Will B, Siddiqi T, Jordà MA, Shimamura T, Luptakova K, Staber PB, Costa DB, Steidl U, Tenen DG, Kobayashi S. Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells. Blood. 2010 Apr 8;115(14):2901-9. PubMed PMID: 20160166; PubMed Central PMCID: PMC2854433.

Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U. Effect of the nonpeptide thrombopoietin receptor agonist eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009 Oct 29;114(18):3899-908. PubMed PMID: 19710504; PubMed Central PMCID: PMC2773490.

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Einstein - Department of Cell Biology

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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
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Chanin Building, Room 401
Bronx, NY 10461

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Research Information