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

被引：417

作者：

Harvey, Richard C. ^{[1
,2
,3
,4
]}

Mullighan, Charles G. ^{[5
]}

Chen, I-Ming ^{[1
,2
,3
,4
]}

Wharton, Walker ^{[1
,2
,3
]}

Mikhail, Fady M. ^{[6
]}

Carroll, Andrew J. ^{[4
,6
]}

Kang, Huining ^{[1
,2
,3
]}

Liu, Wei ^{[7
]}

Dobbin, Kevin K. ^{[8
]}

Smith, Malcolm A. ^{[9
]}

Carroll, William L. ^{[4
,10
,11
,12
,13
]}

Devidas, Meenakshi ^{[4
,14
,15
]}

Bowman, W. Paul ^{[4
,16
]}

Camitta, Bruce M. ^{[4
,17
]}

Reaman, Gregory H. ^{[4
,18
]}

Hunger, Stephen P. ^{[4
,19
,20
]}

Downing, James R. ^{[5
]}

Willman, Cheryl L. ^{[1
,2
,3
,4
]}

机构：

[1] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA

[2] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA

[3] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA

[4] Childrens Oncol Grp, Arcadia, CA USA

[5] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA

[6] Univ Alabama, Dept Genet, Birmingham, AL USA

[7] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA

[8] Univ Georgia, Coll Publ Hlth, Athens, GA 30602 USA

[9] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA

[10] NYU, Med Ctr, Dept Pediat, New York, NY 10003 USA

[11] NYU, Med Ctr, Dept Hematol, New York, NY 10003 USA

[12] NYU, Med Ctr, Dept Oncol, New York, NY 10003 USA

[13] NYU, Med Ctr, Ctr Canc, New York, NY 10003 USA

[14] Univ Florida, Coll Med, Childrens Oncol Grp Stat & Data Ctr, Gainesville, FL USA

[15] Univ Florida, Coll Med, Dept Epidemiol & Hlth Policy Res, Gainesville, FL USA

[16] Cook Childrens Med Ctr, Ft Worth, TX USA

[17] Med Coll Wisconsin, Dept Pediat Hematol Oncol & Transplantat, Milwaukee, WI 53226 USA

[18] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA

[19] Univ Colorado, Denver Sch Med, Childrens Hosp, Dept Pediat, Aurora, CO USA

[20] Univ Colorado, Denver Sch Med, Ctr Canc, Aurora, CO USA

来源：

BLOOD | 2010年 / 115卷 / 26期

基金：

美国国家卫生研究院;

关键词：

THYMIC STROMAL LYMPHOPOIETIN; MINIMAL RESIDUAL DISEASE; IN-VITRO; MYELOPROLIFERATIVE DISORDERS; CLINICAL-SIGNIFICANCE; RISK CLASSIFICATION; MOLECULAR-GENETICS; CELL DEVELOPMENT; COMPETING RISK; RECEPTOR;

D O I：

10.1182/blood-2009-09-245944

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. This trial was registered at www.clinicaltrials.gov as #NCT00005603. (Blood. 2010;115(26):5312-5321)

引用

页码：5312 / 5321

页数：10

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