Infections increase the risk of cancer; yet the pathophysiologic basis for this association remains poorly understood. Our long term goal is to improve cancer prevention by defining the molecular mechanisms by which infections promote cancer. We have chosen to study blood in order to capitalize on existing tools and knowledge in the field of hematopoietic stem cells (HSCs) and blood cancers. Our prior work has established that inflammatory signals released during infection exert strong activation pressure on quiescent HSCs, inducing them to divide and differentiate. Persistent inflammatory stress leads to HSC exhaustion. Notably, HSCs are not a homogeneous population, and inflammatory signals exhaust responsive subsets of HSCs more quickly than others. In the case of acute myelogenous leukemia (AML), sporadic founder mutations have been identified and these define HSC subpopulations with varying propensity for leukemic transformation. Mutations in the tumor suppressor DNA methyltransferase 3A (DNMT3A) are the most common founder mutation in AML, and analogous mutations in murine Dnmt3a have been shown to impair differentiation while enhancing self-renewal. In humans, DNMT3A-mutant clones expand in the marrow, leading to clonal hematopoiesis in up to 10% of all people over the age of 65. DNMT3A-mutant clonal hematopoiesis is associated with an increased risk of leukemic transformation. Using an innovative mosaic animal model, we find that chronic infection accelerates the expansion of Dnmt3a-mutant preleukemic clones in a WT mouse to three times the normal rate. We therefore hypothesize that infection accelerates the expansion of preleukemic Dnmt3a-mutant HSCs by inducing terminal differentiation of WT HSCs, thereby providing a selection advantage for the mutant clones.
In Aim 1 we will ascertain what inflammatory signals and what types of infections promote Dnmt3a-mutant HSC expansion in our mosaic animal model.
In Aim 2 we will determine whether differences between Dnmt3a-mutant and WT HSCs in cell division, cell death, or differentiation account for expansion of the mutant clone. We will use these findings to optimize a mathematical model that can be used to predict the effects of changes in those factors on preleukemic clonal expansion. Finally, in Aim 3 we will use gain-of-function and loss-of-function studies to identify molecular drivers of Dnmt3a-mutant HSC expansion among candidates selected from prior transcriptome screening. The overall impact of these studies is that they will reveal essential mechanistic information about the role of infections in preleukemic clonal expansion that will form the basis for future work to design specific therapeutic interventions to prevent cancer emergence.

Public Health Relevance

Infections increase the risk for cancer, but the pathologic basis for this association remains poorly understood. Using a preclinical model, we now find that infection accelerates the expansion of premalignant stem cells relative to normal stem cells. By defining the mechanistic basis for this expansion, we will identify specific molecular targets to interrupt this process and reveal a novel strategy for cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL136333-04
Application #
9921465
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bai, C Brian
Project Start
2017-05-01
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Matatall, Katie A; Kadmon, Claudine S; King, Katherine Y (2018) Detecting Hematopoietic Stem Cell Proliferation Using BrdU Incorporation. Methods Mol Biol 1686:91-103
Yan, Hannah; Baldridge, Megan T; King, Katherine Y (2018) Hematopoiesis and the bacterial microbiome. Blood 132:559-564
Morales-Mantilla, Daniel E; King, Katherine Y (2018) The Role of Interferon-Gamma in Hematopoietic Stem Cell Development, Homeostasis, and Disease. Curr Stem Cell Rep 4:264-271
Kadmon, Claudine S; Landers, Cameron T; Li, Haiyan S et al. (2017) MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice. Exp Hematol 56:7-15