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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.
Blood 2010; 115(26):5312-21Blood

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+Show Affiliations

University of New Mexico Cancer Center and Departments of Pathology and Internal Medicine, University of New Mexico, Albuquerque, NM, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20139093

Citation

Harvey, Richard C., et al. "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." Blood, vol. 115, no. 26, 2010, pp. 5312-21.
Harvey RC, Mullighan CG, Chen IM, et al. 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. Blood. 2010;115(26):5312-21.
Harvey, R. C., Mullighan, C. G., Chen, I. M., Wharton, W., Mikhail, F. M., Carroll, A. J., ... Willman, C. L. (2010). 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. Blood, 115(26), pp. 5312-21. doi:10.1182/blood-2009-09-245944.
Harvey RC, et al. 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. Blood. 2010 Jul 1;115(26):5312-21. PubMed PMID: 20139093.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Harvey,Richard C, AU - Mullighan,Charles G, AU - Chen,I-Ming, AU - Wharton,Walker, AU - Mikhail,Fady M, AU - Carroll,Andrew J, AU - Kang,Huining, AU - Liu,Wei, AU - Dobbin,Kevin K, AU - Smith,Malcolm A, AU - Carroll,William L, AU - Devidas,Meenakshi, AU - Bowman,W Paul, AU - Camitta,Bruce M, AU - Reaman,Gregory H, AU - Hunger,Stephen P, AU - Downing,James R, AU - Willman,Cheryl L, Y1 - 2010/02/04/ PY - 2010/2/9/entrez PY - 2010/2/9/pubmed PY - 2010/8/3/medline SP - 5312 EP - 21 JF - Blood JO - Blood VL - 115 IS - 26 N2 - 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. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/20139093/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_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&amp;pmid=20139093 DB - PRIME DP - Unbound Medicine ER -