Activation of Paired-Homeobox Gene PITX1 by Del(5)(q31) In T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Abstract 4644

Aberrant activation of various oncogenes, including homeobox genes encoding fundamental transcription factors, during T-cell development contributes to T-cell acute lymphoblastic leukemia (T-ALL). Neoplastic chromosome rearrangements are known to deregulate Antennapedia-class homeobox genes of the NKL-family (TLX1, TLX3, NKX2-5) and HOXA-cluster genes of the Extended-Hox-family. Following analysis of T-ALL cell lines and primary cells, we describe leukemogenic involvement of a third homeobox gene group, the Paired (PRD)-class. Ascertainment was performed in an early stage-arrested T-ALL cell line (LOUCY) which revealed chromosomal deletion at 5q31, removing the downstream regulatory region of the PRD-homeobox gene PITX1. Comparative expression analysis confirmed ectopic PITX1 expression, consistent with aberrant activation by del(5)(q31) which removes a STAT1 binding site. STAT1 mediates repressive IL2-STAT1 signaling, implicating IL2-pathway avoidance as a possible activation mechanism. Furthermore, we detected expression of the physiologically similar PITX2 in 11/24 (46%) T-ALL cell lines, 5 with genomic PITX2 gains. Among primary T-ALL samples, 2/22 (9%) – both pediatric pre-T-ALL - ectopically expressed PITX1 but not PITX2. Forced expression of PITX1 by lentiviral transduction of JURKAT cells and subsequent analysis by expression profiling, prompted upregulation of RUNX2 and JUN and inhibition of RUNX1 and NKX3-1, indicating impaired T-cell differentiation. Taken together, our data show leukemic activation of PITX1, a novice PRD-class homeobox gene in the T-ALL repertoire, which may promote leukemogenesis by inhibiting differentiation.