The goal of this project is to elucidate the mechanisms by which the AP-1 transcription factor JunB regulates normal hematopoiesis, and to understand how loss of JunB alters hematopoietic stem cells (HSC) properties and leads to the generation of leukemic stem cells (LSC). These studies will be carried out in mouse models of JunB deficiency that we have generated and characterized. Studies in Specific Aim 1 will investigate how deregulated cell cycle distribution and increased proliferation contribute to the aberrant properties of junB- deficient HSC. We will determine to what extent quiescent vs. cycling junB-deficient HSC are able to provide long-term engraftment, investigate their response to hematopoietic stresses and interrogate the molecular networks controlling their proliferation. These experiments should address the question of how HSC maintenance and proliferation are co-coordinately regulated to ensure homeostasis and how changes innts should increase our understanding of how HSC are maintained in their bone marrow niches and how LSC can escape these microenvironmental regulations. The general goal of Specific Aim 3 is to identify junB target genes in HSC. We will exploit both genome-wide bioinformatics approach to scan for genes with cis-regulatory motifs matching canonical JunB binding sites and chromatin immunoprecipitation (ChIP) approach with genomic array platforms (ChIP-chip). These experiments should uncover important regulatory networks controlling HSC homeostasis and transcriptional abnormalities underlying LSC generation.
In Specific Aim 4, we will functionally evaluate the contribution of deregulated proliferation and microenvironmental interactions to the leukemic transformation of junB-deficient HSC. We will test the role of several important candidate genes by either correcting their defective regulation in junB-deficient HSC or by mimicking their alterations in normal HSC. These experiments should identify critical mediators that functionally contribute to LSC generation and function. PROJECT NARRATIVE: Together, these experiments pursue the general goal of identifying molecular targets to destroy the otherwise therapeutically resistant LSC population in human myeloid leukemias. ????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092471-05
Application #
8240053
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2008-04-03
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$382,388
Indirect Cost
$134,888
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pietras, Eric M; Mirantes-Barbeito, Cristina; Fong, Sarah et al. (2016) Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol 18:607-18
Wong, Jasmine C; Weinfurtner, Kelley M; Alzamora, Maria Del Pilar et al. (2015) Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis. Elife 4:
Schepers, Koen; Campbell, Timothy B; Passegué, Emmanuelle (2015) Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 16:254-67
Alvarez, Silvia; Díaz, Marcos; Flach, Johanna et al. (2015) Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality. Nat Commun 6:8548
Casbon, Amy-Jo; Reynaud, Damien; Park, Chanhyuk et al. (2015) Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A 112:E566-75
Pietras, Eric M; Reynaud, Damien; Kang, Yoon-A et al. (2015) Functionally Distinct Subsets of Lineage-Biased Multipotent Progenitors Control Blood Production in Normal and Regenerative Conditions. Cell Stem Cell 17:35-46
Pietras, Eric M; Lakshminarasimhan, Ranjani; Techner, Jose-Marc et al. (2014) Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. J Exp Med 211:245-62
Kohli, Latika; Passegué, Emmanuelle (2014) Surviving change: the metabolic journey of hematopoietic stem cells. Trends Cell Biol 24:479-87
Flach, Johanna; Bakker, Sietske T; Mohrin, Mary et al. (2014) Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512:198-202
Bakker, Sietske T; Passegué, Emmanuelle (2013) Resilient and resourceful: genome maintenance strategies in hematopoietic stem cells. Exp Hematol 41:915-23

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