title: Activation of Paired-homeobox gene PITX1 by del(5)(q31) in T-cell acute lymphoblastic leukemia.
abstract: In T-cell acute lymphoblasic leukemia (T-ALL), neoplastic chromosomal rearrangements are known to deregulate members of the homeobox gene families NKL and HOXA. Here, analysis of T-ALL cell lines and primary cells identified aberrant expression of a third homeobox gene group, the Paired (PRD) class. LOUCY cells revealed chromosomal deletion at 5q31, which targets the downstream regulatory region of the PRD homeobox gene PITX1, removing a STAT1 binding site. STAT1 mediates repressive interleukin 2 (IL2)-STAT1 signaling, implicating IL2 pathway avoidance as a possible activation mechanism. Among primary T-ALL samples, 2/22 (9%) aberrantly expressed PITX1, highlighting the importance of this gene. Forced expression of PITX1 in JURKAT cells and subsequent target gene analysis prompted deregulation of genes involved in T-cell development including HES1, JUN, NKX3-1, RUNX1, RUNX2, and TRIB2. Taken together, our data show leukemic activation of PITX1, a novice PRD-class homeobox gene in a subset of early-staged T-ALL, which may promote leukemogenesis by inhibiting T-cell development.
authors.affiliation: Department of Human and Animal Cell Lines, DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany. sna@dsmz.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.forename: Letizia
authors.initials: L
authors.lastname: Venturini
authors.forename: Grzegorz K
authors.initials: GK
authors.lastname: Przybylski
authors.forename: Piotr
authors.initials: P
authors.lastname: Grabarczyk
authors.forename: Björn
authors.initials: B
authors.lastname: Schneider
authors.forename: Corinna
authors.initials: C
authors.lastname: Meyer
authors.forename: Maren
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Christian A
authors.initials: CA
authors.lastname: Schmidt
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: Macleod
mesh_terms: D000293:Adolescent; D000328:Adult; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D019169:Jurkat Cells; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D007376:Interleukin-2; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D051761:Paired Box Transcription Factors; D050794:STAT1 Transcription Factor; C101485:homeobox protein PITX1