title: Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a high incidence of relapse in pediatric ALL. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate the onset of leukemia and worsen disease progression are largely unknown. Here, we show that the gene encoding the transcription factor KLF4 is inactivated by DNA methylation in children with T-ALL. In mice, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL by enhancing the G1-to-S transition in leukemic cells and promoting the expansion of leukemia-initiating cells. Mechanistically, KLF4 represses the gene encoding the kinase MAP2K7. Our results showed that in murine and pediatric T-ALL, loss of KLF4 leads to aberrant activation of MAP2K7 and of the downstream effectors JNK and ATF2. As a proof-of-concept for the development of a targeted therapy, administration of JNK inhibitors reduced the expansion of leukemia cells in cell-based and patient-derived xenograft models. Collectively, these data uncover a novel function for KLF4 in regulating the MAP2K7 pathway in T-ALL cells, which can be targeted to eradicate leukemia-initiating cells in T-ALL patients.
authors.affiliation: Department of Pathology &Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pathology &Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Park
authors.affiliation: Texas Children's Cancer and Hematology Center, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Suppipat
authors.affiliation: Department of Pathology &Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: T-A
authors.initials: TA
authors.lastname: Mistretta
authors.affiliation: Department of Pathology &Immunology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Puppi
authors.affiliation: Texas Children's Cancer and Hematology Center, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Horton
authors.affiliation: Texas Children's Cancer and Hematology Center, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Rabin
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam and the Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: J P P
authors.initials: JPP
authors.lastname: Meijerink
authors.affiliation: Department of Pathology &Immunology, Baylor College of Medicine, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Lacorazza
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency*; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse