ALBERT

Description: Abstract 182 Chromosomal alterations are a hallmark of acute lymphoblastic leukemia (ALL), but many cases lack a recurring cytogenetic abnormality. To identify novel alterations contributing to leukemogenesis, we previously performed genome-wide profiling of genetic alterations in pediatric ALL using single nucleotide polymorphism (SNP) microarrays. This identified a novel focal deletion involving the pseudoautosomal region (PAR1) of Xp/Yp in 15 B-progenitor ALL cases lacking sentinel chromosomal abnormalities, including six of eight cases of ALL associated with Down syndrome (DS-ALL). The deletion involved hematopoietic cytokine receptor genes, including IL3RA and CSF2RA, but due to poor array coverage, it was not possible to define the limits of deletion using SNP array data alone. To characterize this abnormality, we examined an expanded cohort of 329 B-ALL cases, including 22 B-progenitor DS-ALL cases. Strikingly, 12 (55%) DS-ALL cases harbored the PAR1 deletion. Mapping using high density CGH arrays showed the deletion to be identical in each case, and involved a 320kb region extending from intron 1 of the purinergic receptor gene P2RY8 to the promoter of CRLF2 (encoding cytokine receptor like factor 2, or thymic stromal lymphopoietin receptor). The deletion resulted in a novel fusion of the first, non-coding exon of P2RY8 to the entire coding region of CRLF2 in each case. The P2RY8-CRLF2 fusion resulted in elevated expression of CRLF2 detectable by quantitative RT-PCR, and flow cytometric analysis of leukemic cells. One DS-ALL case with elevated CRLF2 expression lacked the PAR1 deletion, but had an IGH@-CRLF2 translocation detected by fluorescence in situ hybridization (FISH). CRLF2 alteration was associated with gain of chromosome X (which was shown by FISH to result in duplication of the PAR1 deletion), deletion of 9p, and the presence of Janus kinase (JAK1 and JAK2) mutations. Ten (53%) of patients with CRLF2 alteration had JAK mutations, compared with two patients lacking CRLF2 abnormalities (P