Transcriptional and Epigenetic Regulation of Pre-Cancerous and Cancer
Stem Cells in Hematopoiesis and Leukemogenesis
Hematopoiesis maintains a life-long supply of the entire spectrum of highly specialized blood cells dependent on systemic needs. This process relies on a tightly regulated balance of self-renewal, commitment, and differentiation of a small number of pluripotent hematopoietic stem cells (HSC).
Recent experimental evidence has shown that acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) arise from transformed immature hematopoietic cells following the accumulation of multiple stepwise genetic and epigenetic changes in HSC and committed progenitors. The series of transforming events initially give rise to pre-leukemic stem cells (pre-LSC), preceding the formation of fully transformed leukemia stem cells (LSC). Pre-LSC as well as LSC are characterized by a relative resistance to chemotherapy and thereby contribute to treatment failure. As a consequence, and despite the established use of poly-chemotherapy and the development of new agents that transiently reduce the tumor burden, relapse continues to be the most common cause of death in most subtypes of AML and MDS. Defining the molecular characteristics and regulatory mechanisms in pre-LSC and their progression to fully transformed LSC is critical to understanding the genesis of leukemia and to developing therapeutic strategies by which these cells can be eradicated.
Recent findings from our own group and others have demonstrated a critical role of key transcriptional regulators, chromatin-remodeling factors, and mediators of aberrant signaling in the genesis and function of pre-LSC and LSC in AML and MDS in mouse and human model systems.
The goal of our research is to delineate critical mechanisms in HSC that drive formation and function of pre-LSC and LSC. To identify and functionally study implicated pathways we are utilizing rigorously defined stem and progenitor cell subsets isolated by means of multi-parameter high-speed fluorescence-activated cell sorting (FACS). Identified target genes are biochemically and functionally tested. We utilize lentiviral gene transfer allowing for forced expression or shRNA-mediated knockdown, followed by in vitro as well as in vivo assays for stem and progenitor cell functions including murine transplantation models. This allows for assessing the function of candidate genes in normal and leukemic stem cells. We are studying murine genetic models as well as primary human samples from patients with leukemia. Our studies ultimately aim at the development of targeted, pre-LSC- and LSC-directed therapies.
Selection of publications since 2012 (from a total of 95):
Stanley RF*, Piszczatowski RT*, Bartholdy B, Mitchell K, McKimpson WM, Narayanagari SR, Walter D, Todorova TI, Hirsch C, Makishima H, Will B, McMahon C, Gritsman K, Maciejewski JP, Kitsis RN, Steidl U.
A myeloid tumor suppressor role for NOL3.
J Exp Med. 2017 (in press)
Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski J, Verma A, Steidl U.
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
Nat Chem Biol. 2015; 11:878-886
Will B*, Vogler TO*, Narayanagari S, Bartholdy B, Todorova TI, da Silva Ferreira M, Chen J, Yu Y, Mayer J, Barreyro L, Carvajal L, Ben Neriah D, 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; 21:1172-1181
Pandolfi A*, Stanley RF*, Yu Y, Bartholdy B, Pendurti G, Gritsman K, Boultwood J, Chernoff J, Verma A, Steidl U.
PAK1 is a Therapeutic Target in Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Blood. 2015; 126:1118-27
Bartholdy B*, Christopeit M*, Will B, Mo Y, Barreyro L, Yu Y, Bhagat TD, Okoye-Okafor UC, Todorova TI, Greally JM, Levine RL, Melnick A, Verma A#, Steidl U#.
A human hematopoietic stem cell-commitment related DNA cytosine methylation signature is prognostic for overall survival in acute myeloid leukemia.
J Clin Invest. 2014; 124:1158-1167
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.
Special AT-rich Sequence-Binding Protein 1 (Satb1) regulates hematopoietic stem cell self-renewal by promoting quiescence and repressing differentiation commitment.
Nat Immunol. 2013; 14:437-45
Kawahara M*, Pandolfi A*, Bartholdy B*, Barreyro L, Will B, Roth M, Okoye-Okafor UC, Todorova TI, Figueroa ME, Melnick A, Mitsiades CS, Steidl U.
H2.0-like Homeobox (HLX) Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia.
Cancer Cell. 2012; 22:194–208
Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C, Tamari R, Yu Y, Bhagat T, Bhattacharya 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*.
Stem and progenitor cells in myelodysplastic syndromes show aberrant stage specific expansion and harbor genetic and epigenetic alterations.
Blood. 2012; 120:2076-2086
Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF, Ben-Neriah S, Montagna C, Parekh S, Pellagatti A, Boultwood J, Paietta E, Ketterling RP, Cripe L, Fernandez HF, Greenberg PL, Tallman MS, Steidl C, Mitsiades CS, Verma A, Steidl U.
Overexpression of interleukin 1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS.
Blood. 2012; 120:1290-1298
Roth M, Will B, Simkin G, Rao S, Barreyro L, Bartholdy B, Tamari R, Mitsiades CS, Verma A, Steidl U.
Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation.
Blood. 2012; 120:386-394
Review Articles and Editorials:
Wheat JC, Steidl U.
ETO2-GLIS2: A chimeric transcription factor drives leukemogenesis through a neomorphic transcription network.
Cancer Cell. 2017 (in press)
Shastri A, Will B, Steidl U*, Verma A*. Stem and Progenitor Cell Alterations in Myelodysplastic Syndromes.
Blood. 2017 (in press)
Carvajal L, Steidl U. Eliminating cancer stem cells in CML with combination transcriptional therapy.
Cell Stem Cell. 2016; 19:6-8
Stanley RF, Steidl U. Molecular mechanism of mutant CALR-mediated transformation.
Cancer Discovery. 2016; 6:344-346
Stanley RF, Steidl U. Ectopic Dnmt3b Expression Delays Leukemogenesis.
Blood. 2016; 127:1525-6
Antony-Debre I, Steidl U.
Functionally relevant RNA helicase mutations in familial and sporadic myeloid malignancies.
Cancer Cell. 2015; 27:609-611
Verma A, Steidl U.
A synthetic lethal approach targeting mutant isocitrate dehydrogenase in acute myeloid leukemia.
Nat Med. 2015;21:113-114
Will B, Steidl U.
Combinatorial haplo-deficient tumor suppression in 7q-deficient myelodysplastic syndrome and acute myeloid leukemia.
Cancer Cell. 2014; 25:555-557
Will B, Steidl U.
Stem cell fate regulation by dynein motor protein Lis1.
Nat Genet. 2014; 46:217-218
Antony-Debre I, Steidl U.
CDK6, a new target in MLL-driven leukemia.
Blood. 2014; 124:5-6
Elias HK, Schinke C, Bhattacharyya S, Will B, Verma A, Steidl U.
Stem cell origin of myelodysplastic syndromes.
Oncogene. 2013 Dec 16. doi: 10.1038/onc.2013.520
Pandolfi A, Barreyro L, Steidl U.
Pre-leukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells.
Stem Cells Transl Med. 2013; 2:143–150
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