Myelodysplastic syndromes (MDS) are hematologic malignancies originating from a defective hematopoietic stem cell (HSC), and defined by blood cytopenias due to ineffective hematopoiesis, a predisposition to acute myeloid leukemia (AML), and genomic instability. We recently identified miR-146a, a microRNA that is part of the deleted segment of chromosome 5q in MDS (del(5q)). Reduced expression of miR-146a, either in del(5q) or normal karyotype MDS, results in increased protein expression of TRAF6, a key target of miR-146a and a mediator of innate immune signaling. Therefore, we hypothesize that chronic innate immune signaling (mediated by TRAF6) contributes to MDS and progression to AML in part by reprogramming the metabolic state of HSC. We also propose that innate immune pathway inhibition will suppress MDS- and AML-propagating cells. Based on these observations, we will (1) define the role of chronic innate immune signaling via TRAF6 in HSC during the progression from MDS to AML, (2) determine the oncogenic dependency of MDS/AML on TRAF6, and (3) investigate HSC metabolic reprograming in MDS HSC. The complexity of MDS and paucity of mouse models are obstacles to effectively treating this disease. The identification of TRAF6 mechanisms in MDS will impact diagnosis, molecular staging, and targeted therapy for MDS/AML, and illuminate a novel and clinically-relevant connection between TRAF6 and metabolic reprogramming via AKT and/or NF-?B in MDS.

Public Health Relevance

Myelodysplastic syndromes (MDS) are a collection of acquired or inherited diseases wherein the bone marrow produces too few blood cells, and patients progress to acute leukemia. We have identified that increased innate immune pathway activation is a common feature in MDS cells. Central to this pathway, TRAF6, may play a role in the abnormal production of blood cells and progression to leukemia. This grant is designed to understand the function of TRAF6 and to determine its role in causing MDS and leukemia using mouse models and patient-derived samples.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114582-01A1
Application #
8760446
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Di Fronzo, Nancy L
Project Start
2014-08-01
Project End
2018-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Gentner, Bernhard; Pochert, Nicole; Rouhi, Arefeh et al. (2015) MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia. Exp Hematol 43:858-868.e7
Gañán-Gómez, I; Wei, Y; Starczynowski, D T et al. (2015) Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia 29:1458-69
Adams, Allie K; Bolanos, Lyndsey C; Dexheimer, Phillip J et al. (2015) IRAK1 is a novel DEK transcriptional target and is essential for head and neck cancer cell survival. Oncotarget 6:43395-407
Varney, Melinda E; Niederkorn, Madeline; Konno, Hiroyasu et al. (2015) Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med 212:1967-85
Varney, Melinda E; Melgar, Katelyn; Niederkorn, Madeline et al. (2015) Deconstructing innate immune signaling in myelodysplastic syndromes. Exp Hematol 43:587-98
Rhyasen, G W; Wunderlich, M; Tohyama, K et al. (2014) An MDS xenograft model utilizing a patient-derived cell line. Leukemia 28:1142-5
Beverly, Levil J; Starczynowski, Daniel T (2014) IRAK1: oncotarget in MDS and AML. Oncotarget 5:1699-700
Rhyasen, Garrett W; Bolanos, Lyndsey; Starczynowski, Daniel T (2013) Differential IRAK signaling in hematologic malignancies. Exp Hematol 41:1005-7
Fang, Jing; Varney, Melinda; Starczynowski, Daniel T (2012) Implication of microRNAs in the pathogenesis of MDS. Curr Pharm Des 18:3170-9