Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.

Abstract

Gene expression profiling of 207 uniformly treated children with high-risk B-progenitor acute lymphoblastic leukemia revealed 29 of 207 cases (14%) with markedly elevated expression of CRLF2 (cytokine receptor-like factor 2). Each of the 29 cases harbored a genomic rearrangement of CRLF2: 18 of 29 (62%) had a translocation of the immunoglobulin heavy chain gene IGH@ on 14q32 to CRLF2 in the pseudoautosomal region 1 of Xp22.3/Yp11.3, whereas 10 (34%) cases had a 320-kb interstitial deletion centromeric of CRLF2, resulting in a P2RY8-CRLF2 fusion. One case had both IGH@-CRLF2 and P2RY8-CRLF2, and another had a novel CRLF2 rearrangement. Only 2 of 29 cases were Down syndrome. CRLF2 rearrangements were significantly associated with activating mutations of JAK1 or JAK2, deletion or mutation of IKZF1, and Hispanic/Latino ethnicity (Fisher exact test, P < .001 for each). Within this cohort, patients with CRLF2 rearrangements had extremely poor treatment outcomes compared with those without CRLF2 rearrangements (35.3% vs 71.3% relapse-free survival at 4 years; P < .001). Together, these observations suggest that activation of CRLF2 expression, mutation of JAK kinases, and alterations of IKZF1 cooperate to promote B-cell leukemogenesis and identify these pathways as important therapeutic targets in this disease.

• Authors: Richard C Harvey, Charles G Mullighan, I-Ming Chen, Walker Wharton, Fady M Mikhail, Andrew J Carroll, Huining Kang, Wei Liu, Kevin K Dobbin, Malcolm A Smith, William L Carroll, Meenakshi Devidas, W Paul Bowman, Bruce M Camitta, Gregory H Reaman, Stephen P Hunger, James R Downing, Cheryl L Willman
• Journal: Blood (Blood) Vol. 115 Issue 26 Pg. 5312-21 (Jul 01 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20139093 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CRLF2 protein, human
• IKZF1 protein, human
• Receptors, Cytokine
• Ikaros Transcription Factor
• Janus Kinase 1
• Janus Kinase 2
• Janus Kinases

Topics

• Adolescent
• Child
• Cohort Studies
• Female
• Gene Expression Regulation, Leukemic
• Hispanic or Latino (genetics)
• Humans
• Ikaros Transcription Factor (genetics)
• Janus Kinase 1 (genetics)
• Janus Kinase 2 (genetics)
• Janus Kinases (genetics)
• Kaplan-Meier Estimate
• Male
• Mutation
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (epidemiology, genetics)
• Receptors, Cytokine (genetics)