The overall goal of this project is to unravel how long-term hematopoietic stem cells (HSCLT) overproduce specific lineages of mature blood cells in disease conditions. In particular, we are interested in identifying the mechanisms responsible for the aberrant production of myeloid cells from transformed HSCLT to uncover novel molecular targets for the treatment of myeloid malignancies such as myeloproliferative neoplasms (MPN). This proposal is based on a novel model of early blood lineage specification we are currently developing in our laboratory in which specific HSCLT differentiation pathways facilitate the production of myeloid cells independently of the lymphoid lineage. We recently discovered two new populations of myeloid-biased multipotent progenitors (MPPs) that normally serve as transient compartments of myeloid amplification but are aberrantly expanded during MPN development. We propose that the hijacking of this myeloid-specific HSCLT differentiation pathway fuels the overproduction of myeloid cells in MPNs, and predict that blockade of its pathological activation may correct aberrant myeloid cell production in disease conditions. We will test these hypotheses using an inducible Scl-tTA:TRE-BCR/ABL (tTA-BA) mouse model of human chronic myelogenous leukemia (CML) that we have extensively characterized in our laboratory (Reynaud et al., 2011). Based on our preliminary data and already published results, we will investigate how cell intrinsic deregulations in the mechanisms controlling HSCLT fate decisions, such as impaired Notch pathway activity, cooperate with changes in the bone marrow (BM) environment, such as increased levels of pro-inflammatory cytokines, to drive MPN development.
In Specific Aim 1, we will address how aberrant activation of HSCLT differentiation pathways leads to myeloid expansion, and will dissect the role of Notch signaling in this process.
In Specific Aim 2, we will investigate how pro-inflammatory signals control HSCLT differentiation pathways in both normal and disease conditions, and will probe for potential crosstalk with Notch signaling.
In Specific Aim 3, we will test whether manipulating HSCLT differentiation pathways by blocking the mechanisms responsible for their aberrant activation could rep- resent a valid approach to treat MPNs. We will perform proof-of-principle experiments in mice and validate key findings using normal human cells and MPN patient samples. Taken together, these approaches will uncover how changes in early blood lineage specification contribute to MPN development, and provide rationales for the clinical use of HSC-based anti-differentiation therapies to treat myeloid malignancies.

Public Health Relevance

A major barrier to developing effective therapeutic interventions for blood disorders is our lack of understanding of what causes long-term hematopoietic stem cells (HSCLT) to overproduce specific types of mature blood cells in disease conditions. Our research project seeks to remove this critical roadblock by investigating how aberrant activation of myeloid-specific differentiation pathways in transformed HSCLT contributes to the development of myeloproliferative neoplasms (MPN) such as chronic myelogenous leukemia (CML). Our experiments address the exciting possibility that manipulating HSCLT differentiation pathways could represents a powerful approach to treat myeloid malignancies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL092471-09
Application #
9064827
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Thomas, John
Project Start
2008-04-03
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
9
Fiscal Year
2016
Total Cost
Indirect Cost
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
94118
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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
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
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