title: Deletion of TAK1 in the myeloid lineage results in the spontaneous development of myelomonocytic leukemia in mice.
abstract: Previous studies of the conditional ablation of TGF-β activated kinase 1 (TAK1) in mice indicate that TAK1 has an obligatory role in the survival and/or development of hematopoietic stem cells, B cells, T cells, hepatocytes, intestinal epithelial cells, keratinocytes, and various tissues, primarily because of these cells' increased apoptotic sensitivity, and have implicated TAK1 as a critical regulator of the NF-κB and stress kinase pathways and thus a key intermediary in cellular survival. Contrary to this understanding of TAK1's role, we report a mouse model in which TAK1 deletion in the myeloid compartment that evoked a clonal myelomonocytic cell expansion, splenomegaly, multi-organ infiltration, genomic instability, and aggressive, fatal myelomonocytic leukemia. Unlike in previous reports, simultaneous deletion of TNF receptor 1 (TNFR1) failed to rescue this severe phenotype. We found that the features of the disease in our mouse model resemble those of human chronic myelomonocytic leukemia (CMML) in its transformation to acute myeloid leukemia (AML). Consequently, we found TAK1 deletion in 13 of 30 AML patients (43%), thus providing direct genetic evidence of TAK1's role in leukemogenesis.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Lamothe
authors.forename: Yunju
authors.initials: Y
authors.lastname: Lai
authors.forename: Lana
authors.initials: L
authors.lastname: Hur
authors.forename: Natalia Martin
authors.initials: NM
authors.lastname: Orozco
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Alejandro D
authors.initials: AD
authors.lastname: Campos
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Lockworth
authors.forename: Jared
authors.initials: J
authors.lastname: Jakacky
authors.forename: Diep
authors.initials: D
authors.lastname: Tran
authors.forename: Michael
authors.initials: M
authors.lastname: Ho
authors.forename: Sity
authors.initials: S
authors.lastname: Dawud
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Hu
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bueso-Ramos
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology; D005434:Flow Cytometry; D017353:Gene Deletion; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013163:Splenomegaly / Q000235:genetics; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D000099151:MAP Kinase Kinase Kinase 7