title: Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling.
abstract: TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Varney
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 Department of Biological Sciences, University of Cincinnati, Cincinnati, OH 45267.
authors.forename: Madeline
authors.initials: M
authors.lastname: Niederkorn
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology and Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Konno
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology and Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology and Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Gohda
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology and Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology and Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Susanne
authors.initials: S
authors.lastname: Christie
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.affiliation: Michael Smith Genome Sciences Centre and Department of Pathology and Laboratory Medicine, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada Michael Smith Genome Sciences Centre and Department of Pathology and Laboratory Medicine, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Ruhikanta A
authors.initials: RA
authors.lastname: Meetei
authors.affiliation: Division of Cellular and Molecular Biology, Department of Cancer Biology and Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, the University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Inoue
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 Daniel.Starczynowski@cchmc.org.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002895:Chromosomes, Human, Pair 5; D006410:Hematopoiesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D011506:Proteins; C544759:TIFAB protein, mouse; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; D051193:Toll-Like Receptors