Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions

Teresa Sadras, Susan L Heatley, Chung H Kok, Yen Dang, Kate M Galbraith, Barbara J McClure, Walter Muskovic, Nicola C. Venn, Sarah Moore, Michael Osborn, Tamas Revesz, Andrew S Moore, Timothy P Hughes, David Yeung, Rosemary Sutton, Deborah L White

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Abstract

CRLF2-rearrangements (CRLF2-r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph+ ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2-r ALL. We performed thorough genomic characterization of 35 CRLF2-r cases (P2RY8-CRLF2 n=18; IGH-CRLF2 n=17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2-F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA/CD25. In addition, Ph-like CRLF2-r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes (CISH, SOCS1), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2-r cases lacking JAK2-pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2-r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking.

Original languageEnglish
JournalCancer Letters
DOIs
Publication statusE-pub ahead of print - 30 Aug 2017

Keywords

  • Journal Article

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