Acute myeloid leukemia (AMI) is a malignant disease that originates 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 leukemic stem cells (LSC). Similar to normal hematopoietic stem cells (HSC), LSC are quiescent in terms of cell cycle and thus, conventional cytotoxic therapies are not effective against LSC in the majority of cases. However, therapeutic eradication of the LSC within the leukemia clone will be essential for a cure of disease. Therefore, an improved understanding of the molecular pathways that suppress the formation and maintenance of LSC is required for the development of therapies that target LSC rather than the bulk tumor cells (leukemic blasts). Recent findings demonstrate a critical role of transcription factors including PU. 1 and JUNB in the genesis and function of LSC in AML in mice and humans, and that PU.1 and JUNB are already deregulated in the early stem cell compartment. Therefore, the goals of this research project are 1) to clarify the exact mechanism of action of PU.1 and JUNB in AML-LSC, 2) to identify new target genes of PU.1 in stem cells that are important for LSC function, and 3) to identify other functionally critical alterations in the stem cell compartment that underlie the formation and maintenance of LSC in genetically defined subtypes of AML with disruption of transcription factor function. To identify implicated pathways rigorously defined stem and progenitor cell subsets will be isolated by means of multi-parameter high-speed fluorescence-activated cell sorting and then subjected to linear RNA amplification and transcriptional analysis. Identified targets will be functionally tested utilizing serial replating assays as well as murine transplantation models to assess their function in LSC. These studies will provide the basis for the development of LSC-directed therapies that might ultimately lead to a cure of AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA131503-03
Application #
7845084
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mufson, R Allan
Project Start
2008-09-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$249,000
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Will, Britta; Vogler, Thomas O; Narayanagari, Swathi et al. (2015) Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat Med 21:1172-81
Bartholdy, Boris; Christopeit, Maximilian; Will, Britta et al. (2014) HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia. J Clin Invest 124:1158-67
Pandolfi, Ashley; Barreyro, Laura; Steidl, Ulrich (2013) Concise review: preleukemic stem cells: molecular biology and clinical implications of the precursors to leukemia stem cells. Stem Cells Transl Med 2:143-50
Will, Britta; Vogler, Thomas O; Bartholdy, Boris et al. (2013) Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment. Nat Immunol 14:437-45
Volpi, Sabrina A; Verma-Gaur, Jiyoti; Hassan, Rabih et al. (2012) Germline deletion of Igh 3' regulatory region elements hs 5, 6, 7 (hs5-7) affects B cell-specific regulation, rearrangement, and insulation of the Igh locus. J Immunol 188:2556-66
Will, Britta; Zhou, Li; Vogler, Thomas O et al. (2012) Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood 120:2076-86
Kawahara, Masahiro; Pandolfi, Ashley; Bartholdy, Boris et al. (2012) H2.0-like homeobox regulates early hematopoiesis and promotes acute myeloid leukemia. Cancer Cell 22:194-208
Barta, Stefan K; Zou, Yiyu; Schindler, John et al. (2012) Synergy of sequential administration of a deglycosylated ricin A chain-containing combined anti-CD19 and anti-CD22 immunotoxin (Combotox) and cytarabine in a murine model of advanced acute lymphoblastic leukemia. Leuk Lymphoma 53:1999-2003
Barreyro, Laura; Will, Britta; Bartholdy, Boris et al. (2012) Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood 120:1290-8
Roth, Michael; Will, Britta; Simkin, Guillermo et al. (2012) Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation. Blood 120:386-94

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