Steidl Lab  --  Albert Einstein College of Medicine

Research Interests 

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.

Selected recent publications from our lab (out of a total of 118):

Chen J, et al., Nat Med. 2018 Dec 3;
MDS Progression to AML at the Stem Cell Level.

Mitchell K, et al., J Exp Med. 2018; 215:1709-1727
IL1RAP potentiates multiple oncogenic signaling pathways in AML.

Carvajal LA, et al., Sci Transl Med. 2018; 10:eaao3003
Dual Inhibition of MDMX and MDM2 as a Therapeutic Strategy in Leukemia.

Antony-Debre I, et al., J Clin Invest. 2017; 127:4297-4313
Pharmacological Inhibition of the Transcription Factor PU.1 in Leukemia.

Stanley RF, Piszczatowski RT, et al., J Exp Med. 2017; 214:753-771
A myeloid tumor suppressor role for NOL3.

Okoye-Okafor UC, et al., Nat Chem Biol. 2015; 11:878-886
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.

Will B, Vogler TO, et al., Nat Med. 2015; 21:1172-1181
Minimal PU.1 Reduction Induces a Preleukemic State and Promotes Development of Acute Myeloid Leukemia.

Pandolfi A, Stanley RF, et al., Blood. 2015; 126:1128-1127
PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome.

Schinke C, et al., Blood. 2015; 125:3144-3152
IL-8/CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

Bartholdy B, Christopeit M, et al., J Clin Invest. 2014; 124:1158-1167
A human hematopoietic stem cell-commitment related DNA cytosine methylation signature
is prognostic for overall survival in acute myeloid leukemia.

Elias HK et al., Oncogene. 2014; 33:5139-5150 
Stem cell origin of myelodysplastic syndromes.

Will B et al., Nat Immunol. 2013; 14:437-45 
Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and
repressing differentiation commitment.

Pandolfi A, Barreyro L, Steidl U.  Stem Cells Transl Med. 2013; 2:143-150
Pre-leukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells.

Kawahara M, Pandolfi A, Bartholdy B, et al., Cancer Cell. 2012; 22:194-208           
H2.0-like Homeobox (HLX) Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia.

Will B et al., Blood. 2012; 120:2076-2086
Stem and Progenitor Cells in Myelodysplastic Syndromes Show Aberrant Stage Specific Expansion and Harbor Genetic and Epigenetic Alterations.

Barreyro L et al., Blood. 2012; 120:1290-1298
Overexpression of Interleukin 1 Receptor Accessory Protein (IL1RAP) in Stem and Progenitor Cells and Outcome Correlation in AML and MDS.

Roth M et al., Blood. 2012; 120:386-394
Eltrombopag Inhibits the Proliferation of Leukemia Cells via Reduction of Intracellular Iron and Induction of Differentiation.

Will B et al., Blood. 2009; 114:3899-908
Effect of the Nonpeptide Thrombopoietin Receptor Agonist Eltrombopag on Bone Marrow Cell from Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome.

Contact Details: 

Ulrich G. Steidl, M.D., Ph.D.
Dept. of Cell Biology, Department of Medicine (Oncology)
Diane and Arthur B. Belfer Faculty Scholar in Cancer Research

Associate Chair for Translational Research, Department of Oncology

Scientific Director, Division of Hemato-Oncology

Leader, 'Stem Cells, Differentiation and Cancer' Program, Albert Einstein Cancer Center

Director, Stem Cell Isolation and Xenotransplantation Facility,
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research

Albert Einstein College of Medicine / Montefiore Medical Center
Chanin Institute for Cancer Research
, Rm.# 601-605
1300 Morris Park Avenue
New York, NY 10461

Tel. (Office): +1 (718) 430-3437
Tel. (Lab):  +1 (718) 430-8953  
Fax:         + 1(718) 430-8574