Associate Professor, Department of Cell Biology
Associate Professor, Department of Medicine (Oncology)
The Diane and Arthur B. Belfer Faculty Scholar in Cancer Research
Transcriptional and Epigenetic Regulation of Normal and Cancer Stem Cells in Hematopoiesis and Leukemia
Acute myeloid leukemias (AML) are malignant diseases that originate from a single transformed cell which has progressively acquired critical genetic changes that disrupt key growth-regulatory pathways. Despite the established use and optimization of regimens applying polychemotherapy and the development of multiple new agents that are effective at reducing the tumor burden in patients with leukemia, relapse continues to be the most common cause of death in AML. Newer experimental evidence demonstrates that AML arises from a small population of cancer stem cells through a multi-step pathogenetic process, originating in pre-leukemic stem cells (pre-LSC) which then sequentially acquire genetic and epigenetic aberrations towards the formation of fully transformed leukemia stem cells (LSC). Similar to normal hematopoietic stem cells (HSC), pre-LSC and LSC are quiescent in terms of cell cycle and thus, conventional cytotoxic therapies are not effective against them in the majority of cases. However, therapeutic eradication of pre-LSC and LSC will be essential for a cure of disease. Therefore, an improved understanding of the molecular pathways that suppress the formation and maintenance of pre-LSC and LSC is required for the development of therapies that target LSC rather than the bulk tumor cells (leukemic blasts). Recent findings from our own group and others demonstrate a critical role of transcriptional master regulators (e.g. PU.1, HLX, STAT3, SATB1) and surface (co)recpetors (e.g. IL1RAP) in the genesis and function of LSC in AML and MDS, and that transcriptional and epigenetic networks are already deregulated in the earliest definable stem cell compartments.
The goal of our research is to identify critical mechanisms that drive leukemia stem cell (LSC) development and function, and to better understand the mechanisms of how transcriptional regulators (e.g. transcription factors and chromatin-remodeling factors) cause formation of pre-LSC and LSC.
To identify implicated pathways we are utilizing rigorously defined stem and progenitor cell subsets isolated by means of multi-parameter high-speed fluorescence-activated cell sorting. Identified target genes are biochemically and functionally tested using lentiviral gene transfer and in vitro as well as in vivo assays for leukemia stem cell self-renewal and differentiation, including colony-forming assays, serial replating assays, and transplantation models that allow for assessing their function in LSC formation and maintenance. Our studies aim at providing a basis for the development of targeted, stem cell-directed therapies.
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 (in press) * contributed equally
Antony-Debre I, Steidl U.
Functionally relevant RNA helicase mutations in familial and sporadic myeloid malignancies.
Cancer Cell. 2015; 27:609-611.
Schinke C, Giricz O, Li W, Shastri A, Gordon SAK, Barreyro L, Bhagat TD, Bhattacharyya S, Ramachandra N, Bartenstein M, Pellagatti A, Boultwood J, Wickrema A, Yu Y, Will B, Wei S, Steidl U*, Verma A*.
IL-8/CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.
Blood. 2015; 125:3144-3152 * co-corresponding authors
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
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#. * contributed equally, # co-corresponding authors
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, Steidl U.
Stem cell fate regulation by dynein motor protein Lis1.
Nat Genet. 2014; 46:217-218.
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.
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
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
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 *contributed equally
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 *co-corresponding authors
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
Wontakal SN, Guo X, Will B, Shi M, Raha D, Mahajan MC, Weissman S, Snyder M, Steidl U, Zheng D, Skoultchi AI.
A large gene network in immature erythroid cells is controlled by the myeloid and B cell transcriptional regulator PU.1.
PLoS Genetics. 2011; 7:e1001392
Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, Johnson NA, Zhao Y, Telenius A, Ben Neriah S, McPerson A, Meissner B, Okoye UC, Diepstra A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, Huntsman DG, Savage KJ, Rimsza LM, Horsman DE, Staudt LM, Steidl U, Marra MA, Gascoyne RD.
MHC Class II Transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers.
Nature. 2011; 471:377-381
Will B, Steidl U. Multi-parameter fluorescence-activated cell sorting and analysis of stem and progenitor cells in myeloid malignancies.
Best Pract Res Clin Haematol. 2010; 23:391-401.
Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U.
Effect of the non-peptide thrombopoietin receptor agonist eltrmobopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndromes.
Blood. 2009; 114:3899-908.
Steidl U*, Steidl C*, Ebralidze A, Chapuy B, Han HJ, Will B, Rosenbauer F, Becker A, Wagner K, Koschmieder S, Kobayashi S, Costa DB, Schulz T, O'Brien KB, Verhaak RG, Delwel R, Haase D, Trumper L, Krauter J, Kohwi-Shigematsu T, Griesinger F, Tenen DG. *contrib. equally.A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia.
J Clin Invest. 2007; 117:2611-20.
Steidl U, Rosenbauer F, Verhaak RG, Gu X, Ebralidze A, Otu HH, Klippel S, Steidl C, Bruns I, Costa DB, Wagner K, Aivado M, Kobbe G, Valk PJ, Passegue E, Libermann TA, Delwel R, Tenen DG. Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells.
Nature Genetics. 2006; 38:1269-77.
More Information About Dr. Ulrich Steidl
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Chanin Building, Room 606A
Bronx, NY 10461
New Rochelle Patch.com interviews Ulrich Steidl, M.D., Ph.D., about his genetics research that could lead to new treatment options for acute myeloid leukemia patients. Dr. Steidl is assistant professor of medicine and of cell biology and The Diane and Arthur B. Belfer Faculty Scholar in Cancer Research.