title: PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia.
abstract: We have recently reported inactivation of the tyrosine phosphatase PTPN2 (also known as TC-PTP) through deletion of the entire gene locus in ∼ 6% of T-cell acute lymphoblastic leukemia (T-ALL) cases. T-ALL is an aggressive disease of the thymocytes characterized by the stepwise accumulation of chromosomal abnormalities and gene mutations. In the present study, we confirmed the strong association of the PTPN2 deletion with TLX1 and NUP214-ABL1 expression. In addition, we found cooperation between PTPN2 deletion and activating JAK1 gene mutations. Activating mutations in JAK1 kinase occur in ∼ 10% of human T-ALL cases, and aberrant kinase activity has been shown to confer proliferation and survival advantages. Our results reveal that some JAK1 mutation-positive T-ALLs harbor deletions of the tyrosine phosphatase PTPN2, a known negative regulator of the JAK/STAT pathway. We provide evidence that down-regulation of Ptpn2 sensitizes lymphoid cells to JAK1-mediated transformation and reduces their sensitivity to JAK inhibition.
authors.affiliation: Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Tekla
authors.initials: T
authors.lastname: Hornakova
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.forename: Stefan
authors.initials: S
authors.lastname: Constantinescu
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Jules P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.forename: Robin
authors.initials: R
authors.lastname: Foa
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000328:Adult; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002648:Child; D055028:Comparative Genomic Hybridization; D005260:Female; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; D050505:Mutant Proteins; C521114:NUP214-ABL1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C071250:TLX1 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2