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 Sell 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 

Deregulation of hematopoietic stem cell (HSC) fate determination processes has been associated with the loss of immune function, bone marrow failure, and malignant transformation during aging. Despite the growing number of studies providing demonstrating the impact of aging on the functionality of HSCs, very little is known about the processes driving age-related changes and how they contribute to bone marrow failure and leukemogenesis. 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 cells assay systems, exploit lentiviral gene transfer, and apply state-of-the-art molecular biology and next generation sequencing techniques. With our studies we aim to identify mechanisms instructing differentiation stage-specific genetic and epigenetic gene regulation and reveal how they contribute to normal and impaired stem cell function. This knowledge will be instrumental for developing more effective and targeted epigenetic approaches for the treatment of age-related stem cell dysfunction and in tissue engineering.

Currently, we have two major project lines in the laboratory aiming at identifying aberrant molecular mechanisms that predispose aged HSCs to failure and transformation:

Transcriptional dysregulation of hematopoietic stem cells during aging. We have previously demonstrated a major role for a chromatin-remodeling factor, Special AT-rich sequence-binding protein 1 (Satb1), in the regulation of HSC fate determination by orchestrating cell fate choices through modulating gene expression, DNA cytosine methylation patterning and histone modifications. Satb1 is inhibited during aging, which could critically contribute to the linage skewing and other age-related changes at the molecular level in aged HSCs, and in age-related bone marrow failure diseases. Using conditional Satb1 KO mice, mouse models of aging and myeloid leukemia, as well as primary human patient samples, we dissect how transcriptional programs regulating stem cell fate determination are instructed and maintained by Satb1, and how they contribute to the functional decline of stem cells during aging.

Characterization and targeting of aberrant hematopoietic stem cells. Compromised adult HSC function leads to impaired tissue turnover repair and is critically involved in aging-related malignant diseases, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our previous work on cellular and molecular alterations within highly purified hematopoietic stem cell populations in patients with hematologic malignancies, as well as murine models of leukemia uncovered several functionally and clinically relevant gene expression and epigenetic alterations. Importantly, we also demonstrated that a population of aberrant hematopoietic stem cells is not eradicated by current therapeutic regimen and expands before disease relapse. We have established a novel mouse model with minimal reduction of the transcriptional regulator PU.1 in a DNA mismatch repair-deficient background allowing for the longitudinal identification, tracking and characterization of preleukemic stem cells. Exploiting this model, as well as MDS and AML patient-derived primary hematopoietic (stem) cells we will uncover the step-wise molecular and functional stem cell-specific alterations that drive leukemogenesis and could potentially be targeted therapeutically. 

Selected Publications

 Will B*#, Vogler TO*, Narayanagari S, Bartholdy B, Todorova TI, Chen J, Yi Y, Mayer J, daSilva Ferreira M, Barreyro L, Carvajal L, Roth M, van Oers J, Schaetzlein S, McMahon C, Edelmann W, Verma A, Steidl U#.                                                                                                                                          *equal contribution,     #co-crresponding authors                  Minimal reduction of PU.1 is sufficient to induce a preleukemic state and promote development of acute myeloid leukemia                                                                  Nature Medicine 2015   Sep7. doi: 10.1038/nm.3936 [Epub ahead of print]                                                                                

 
Elias H, Schinke C, Bhattacharyya S, Will B*, Verma A.*, Steidl U.*             * co-corresponding authors
Stem cell origin of myelodysplastic syndromes
Oncogene 2013   December 16; advance online publication; doi: 10.1038/onc.2013.520. Review.
 
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 hematopoietic stem cell self-renewal by promoting quiescence and repressing differentiation commitment
Nature Immunology 2013  14(5):437-45.
 
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 J, Ye BH, List A, Steidl C, Steidl U*, Verma A*.           * co-corresponding authors
Stem and progenitor cells in myelodysplastic syndromes show aberrant stage specific expansion and harbor genetic and epigenetic alterations
Blood 2012   120(10):2076-86.
 
Will B and Steidl U.
Multi-parameter fluorescence-activated cell sorting and analysis of stem and progenitor cells in myeloid malignancies
Best Pract Res Clin Haematol 2010    23(3):391-401.  Review.
 
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   115:2901-9.
 
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   114:3899-908.                   Selected and highlighted by the Faculty of 1000 Medicine

More Information About Dr. Britta Will

https://www.einstein.yu.edu/departments/cell-biology/

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Chanin Building, Room 401
Bronx, NY 10461

Tel: 718.430.3786
Fax: 718.430.8574

Research Information