Myelodysplastic syndromes (MDS) are clonal marrow failure disorders defined by blood cytopenias due to ineffective hematopoiesis, genomic instability, and predisposition to leukemia. The most recurring genomic alteration in MDS is deletion of chromosome 5q (del(5q)). Two common deleted regions (CDRs) have been mapped on chr 5q (bands q31.1 and q33.1);however, the genes within the CDRs that contribute to dysplastic myeloid cells or to a survival advantage for hematopoietic stem/progenitor cells (HSPC) have not been identified. We recently identified miR-146a, which is near the distal CDR, to be significantly reduced in del(5q) MDS patients. Loss of miR-146a or overexpression of its target, TRAF6, in HSPC results in an MDS-like disease in mice. A search of annotated genes within or near the CDRs revealed another known inhibitor of TRAF6, TRAF-interacting protein with forkhead-associated domain B (TIFAB), on 5q31.1 (within the proximal CDR). TIFAB binds and inhibits TIFA, a protein essential for TRAF6 activation. We hypothesize that TIFAB deletion results in HSPC defects contributing to del(5q) MDS by promoting hyperactivation of TRAF6, and propose that simultaneous loss of TIFAB and miR-146a synergistically activate TRAF6 in HSPC to induce a more accurate disease. Preliminary data show that RNAi-mediated knockdown or genetic deletion of TIFAB results in MDS-like defects in mice. The objectives of this proposal are (1) to investigate the loss of TIFAB on HSPC function and the contribution to MDS;(2) to determine the consequences of TIFAB deletion on TRAF6 activation, and whether these could explain features of MDS;and (3) to investigate whether deletions of TIFAB and miR-146a cooperate to initiate MDS via TRAF6 activation. Given that the molecular basis of MDS is poorly defined, we hope that characterization of TIFAB will facilitate understanding the molecular defects and the design of novel therapeutics in MDS.

Public Health Relevance

Myelodysplastic syndromes (MDS) are a collection of diseases wherein the bone marrow produces too few blood cells. Most of these patients have a deletion of chromosome 5q. We have identified a gene, TIFAB, on chromosome 5q, that when deleted, may play a role in the abnormal production of blood cells. This grant is designed to understand the function of TIFAB and to determine its role in causing MDS using mouse models.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL111103-01
Application #
8217790
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Di Fronzo, Nancy L
Project Start
2011-12-15
Project End
2016-11-30
Budget Start
2011-12-15
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Fang, Jing; Muto, Tomoya; Kleppe, Maria et al. (2018) TRAF6 Mediates Basal Activation of NF-?B Necessary for Hematopoietic Stem Cell Homeostasis. Cell Rep 22:1250-1262
Fang, Jing; Bolanos, Lyndsey C; Choi, Kwangmin et al. (2017) Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol 18:236-245
Fang, Jing; Bolanos, Lyndsey C; Choi, Kwangmin et al. (2017) Corrigendum: Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat Immunol 18:474
Varney, M E; Choi, K; Bolanos, L et al. (2017) Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome. Leukemia 31:491-495
Fang, Jing; Liu, Xiaona; Bolanos, Lyndsey et al. (2016) A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. Nat Med 22:727-34
Shimizu, Ryo; Muto, Tomoya; Aoyama, Kazumasa et al. (2016) Possible role of intragenic DNA hypermethylation in gene silencing of the tumor suppressor gene NR4A3 in acute myeloid leukemia. Leuk Res 50:85-94
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
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
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
Rhyasen, G W; Starczynowski, D T (2015) IRAK signalling in cancer. Br J Cancer 112:232-7

Showing the most recent 10 out of 18 publications