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Functional Screening Identifies CRLF2 in Precursor B-Cell Acute

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Functional Screening Identifies CRLF2 in Precursor B-Cell Acute Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia Akinori Yodaa, Yuka Yodaa, Sabina Chiarettib, Michal Bar-Natana, Kartik Mania, Scott J. Rodigc, Nathan Westa, Yun Xiaoc, Jennifer R. Browna, Constantine Mitsiadesa, Martin Sattlera, Jeffrey L. Kutokc, Daniel J. DeAngeloa, Martha Wadleigha, Alfonso Piciocchid, Paola Dal Cinc, James E. Bradnera, James D. Griffina, Kenneth C. Andersona, Richard M. Stonea, Jerome Ritza, Robin Foàb, Jon C. Asterc, David A. Franka, and David M. Weinstocka,1 aDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; bDivision of Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University of Rome, 00185 Rome, Italy; cDepartment of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and dGruppo Malattie Ematologiche dell’Adulto Data Center, 00161 Rome, Italy Edited by Ross Levine, Memorial Sloan-Kettering Cancer Center, and accepted by the Editorial Board November 12, 2009 (received for review October 9, 2009) The prognosis for adults with precursor B-cell acute lymphoblastic which is believed to serve as a scaffold. As a consequence, JAK leukemia (B-ALL) remains poor, in part from a lack of therapeutic gain-of-function mutants do not confer a transformed phenotype targets. We identified the type I cytokine receptor subunit CRLF2 in the absence of a compatible cytokine receptor (16). in a functional screen for B-ALL–derived mRNA transcripts that can We performed a retroviral cDNA library screen to identify substitute for IL3 signaling. We demonstrate that CRLF2 is overex- gain-of-function mutations from primary B-ALL specimens. We pressed in approximately 15% of adult and high-risk pediatric B- made several improvements to older approaches that increase ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but the efficiency of library construction and cDNA representation. not in B-ALL with these rearrangements or other lymphoid malig- nancies. CRLF2 overexpression can result from translocation with In addition, we added selection-based clone recovery, which fi the IGH locus or intrachromosomal deletion and is associated with essentially eliminates false-positive ndings. Using this system, poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional we identified CRLF2, a type I cytokine receptor subunit also signature that significantly overlaps with a BCR/ABL signature, and known as thymic stromal lymphopoietin receptor (TSLPR), as a is enriched for genes involved in cytokine receptor and JAK-STAT proto-oncogene in B-ALL. CRLF2 binds its ligand, thymic signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-of- stromal lymphopoietin (TSLP), as part of a heterodimeric function mutation that promotes constitutive dimerization and cy- complex with the IL7 receptor subunit (IL7R) (17). TSLP is tokine independent growth. A mutually exclusive subset harbors produced by epithelial cells at sites of inflammation, where it activating mutations in JAK2. In fact, all 22 B-ALLs with mutant activates myeloid dendritic cells and Th2 immune responses (18, JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 19). TSLP also promotes early B-cell development (20) and as the key scaffold for mutant JAK2 signaling in B-ALL. Expression stimulates the growth of some human B-ALLs in vitro (21). of WT CRLF2 with mutant JAK2 also promotes cytokine independ- CRLF2 ent growth that, unlike CRLF2 Phe232Cys or ligand-induced signal- We demonstrate that overexpression is common only TEL, MLL, TCF3, ing by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, in B-ALL cases that lack rearrangements of cells dependent on CRLF2 signaling are sensitive to small molecule and BCR/ABL (5–8) and confers a poor prognosis among chil- inhibitors of either JAKs or protein kinase C family kinases. Togeth- dren and adults. Similar to recent reports (22, 23), we show that er, these findings implicate CRLF2 as an important factor in B-ALL CRLF2 overexpression can result from locus rearrangement, with diagnostic, prognostic, and therapeutic implications. either translocation or intrachromosomal deletion. We identify CRLF2 Phe232Cys and JAK2 Arg683 gain-of-function muta- JAK2 | TSLPR | TSLP tions in mutually exclusive subsets of CRLF2-overexpressing B- ALL that transform growth factor–dependent cells to factor uring the past decade, studies using oligonucleotide arrays independence. Strikingly, 100% of B-ALL cases with mutant fi Dand high-throughput sequencing have identi ed several JAK2 overexpress CRLF2, suggesting that CRLF2 is the essen- genetic and transcriptional aberrations in B-cell acute lympho- tial, or at least the overwhelmingly predominate, scaffold for blastic leukemia (B-ALL) (1), leading to three conceptual ad- mutant JAK2 activity in B-ALL. Finally, we show that the gene vances. First, genes involved in normal B-cell development (e.g., signature associated with CRLF2 overexpression is highly similar PAX5, IKZF1) are frequently mutated in B-ALL (1–3). Second, in both pediatric and adult cases, and significantly overlaps with a B-ALL is highly heterogeneous and can exist as multiple, ge- netically distinct clones within the same individual (1, 4). Third, BCR/ABL signature. Together, these studies establish CRLF2 as B-ALL transcriptional profiles cluster based on characteristic a key factor in B-ALL, and support its use as a prognostic and chromosomal rearrangements, hereafter defined as rearrange- therapeutic target. ments of TEL, MLL, TCF3, and BCR/ABL (5–8). However, one third of B-ALL cases lack characteristic rear- fi rangements (9). Transcriptional pro les from a subset of these Author contributions: A.Y., S.C., K.M., S.J.R., J.B., C.S.M., J.D.G., J.R., J.C.A., D.A.F., and leukemias cluster with profiles from BCR/ABL–expressing B- D.M.W. designed research; A.Y., Y.Y., S.C., M.B.-N., K.M., S.J.R., N.W., Y.X., J.B., C.S.M., and ALL (3, 5), suggesting that the former harbor cryptic alterations P.S.D.C. performed research; S.C., M.B.-N., S.J.R., M.S., J.L.K., D.J.D., M.W., J.E.B., J.D.G., K.C.A., R.M.S., R.F., J.C.A., and D.A.F. contributed new reagents/analytic tools; A.Y., K.M., in tyrosine kinase signaling. Supporting this notion, mutations in S.J.R., N.W., J.B., C.S.M., A.P., P.S.D.C., J.E.B., D.A.F., and D.M.W. analyzed data; and A.Y., JAKs were recently identified in a small percentage of pediatric J.C.A., D.A.F., and D.M.W. wrote the paper. B-ALL and approximately 20% of ALL in children with Down The authors declare no conflict of interest. – syndrome (10 14). This article is a PNAS Direct Submission. R.L. is a guest editor invited by the Editorial Upon ligand binding to a type I cytokine receptor, JAKs phos- Board. phorylate substrates including STATs, which in turn affect the 1To whom correspondence should be addressed. E-mail: [email protected]. transcription of progrowth and antiapoptotic factors (15). JAK This article contains supporting information online at www.pnas.org/cgi/content/full/ enzymatic activity requires interaction with a cytokine receptor, 0911726107/DCSupplemental. 252–257 | PNAS | January 5, 2010 | vol. 107 | no. 1 www.pnas.org/cgi/doi/10.1073/pnas.0911726107 Downloaded by guest on September 27, 2021 Results A CRLF2 overexpression Mutated CRLF2 Is a Gain-of-Function Oncoprotein in Poor-Prognosis Yes (n=15), range No (n=75), range p value fi Median age (years) 32.5, 19.3-67.1 34.3, 15.5-64.8 0.92 B-ALL. We identi ed CRLF2 in a functional screen for leukemia- WBC (x103/µL) 1 26.9, 1.9-422.0 20.2, 1.4-357.0 0.42 derived cDNA that activate tyrosine kinase signaling (Fig. 1A). Male:Female 11:4 41:34 0.25 In this screen, we infect the murine IL3-dependent cell line BaF3 Median overall 25.5 months Not reached with retroviral cDNA libraries constructed from bone marrow survival Median disease- 17.8 months 37.8 months aspirates involved with more than 80% tumor. Clones that sur- free survival vive IL3 withdrawal invariably harbor tumor-derived cDNAs that obviate the requirement for IL3. After infection with a cDNA Disease-free survival Overall survival B 100 library constructed from a B-ALL specimen with 46, XY kar- p=0.0246 p=0.1738 yotype, we identified IL3-independent clones that contained a CRLF2 80 CRLF2 low/no mutated, full-length cDNA transcript of . expression (n=75) We used a combination of quantitative (q) RT-PCR, immu- 60 CRLF2 low/no fi expression (n=75) nohistochemistry (IHC), and gene expression pro ling (GEP) to 40 CRLF2 high assay CRLF2 expression in adult B-ALL samples from Dana- expression (n=15) 20 CRLF2 high Farber Cancer Institute (DFCI; n = 97) and Gruppo Malattie expression (n=15) Ematologiche dell’Adulto (GIMEMA; n = 157) cohorts (Fig. 1B (%) Proportion remaining 0 Months 020 40 60 80 100 020 40 60 80 100 and Fig. S1). Cases with CRLF2 overexpression were clearly distinct, and overexpression correlated completely between as- Fig. 2. Demographic and outcome analysis for patients with B-ALL that lack says (Fig. 1B and Fig. S1). Overall, CRLF2 was overexpressed in characteristic rearrangements, based on CRLF2 expression. (A) A comparison 15 of 120 (12.5%) adult B-ALL cases that lacked characteristic of 90 adult patients with B-ALL who lack characteristic cytogenetic re- = = gene rearrangements, compared with 0 of 134 with these re- arrangements, pooled from GIMEMA (n 70) and DFCI specimens (n 20). All − values are at the time of diagnosis. Median follow-up for the full cohort is 39.4 arrangements (P < 10 4).
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