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Tumor Suppressor Gene Cooperates with BCR-ABL in a Transgenic Model of Acute Lymphoblastic Leukemia

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Tumor Suppressor Gene Cooperates with BCR-ABL in a Transgenic Model of Acute Lymphoblastic Leukemia Letters to the Editor 1200 1 2 1 3 SRo¨ttgers , M Gombert , A Teigler-Schlegel , K Busch , 2 Bullrich F, Morris SW, Hummel M, Pileri S, Stein H, Croce CM. 4 5 1 2 U Gamerdinger , R Slany , J Harbott and A Borkhardt Nucleophosmin (NPM) gene rearrangements in Ki-1-positive 1Department of Pediatric Hematology and Oncology, lymphomas. Cancer Res 1994; 54: 2873–2877. Oncogenetic Laboratory, University Hospital, Justus Liebig 3 Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S University Giessen, Giessen, Germany; et al. Identification of the transforming EML4-ALK fusion gene in 2Clinic of Pediatric Hematology, Oncology and Clinical non-small-cell lung cancer. Nature 2007; 448: 561–566. Immunology, Heinrich-Heine University Duesseldorf, 4 Jazii FR, Najafi Z, Malekzadeh R, Conrads TP, Ziaee AA, Duesseldorf, Germany; Abnet C et al. Identification of squamous cell carcinoma asso- 3Hessian State Office of Criminal InvestigationFWiesbaden, ciated proteins by proteomics and loss of beta tropomyosin Wiesbaden, Germany; expression in esophageal cancer. World J Gastroenterol 2006; 12: 4Department of Pathology, University Hospital, Giessen, 7104–7112. Germany and 5 Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The 5 anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Department of Genetics, Friedrich-Alexander University Cancer 2008; 8: 11–23. Erlangen, Erlangen, Germany 6 Trumper L, Pfreundschuh M, Bonin FV, Daus H. Detection of the E-mail: [email protected] t(2;5)-associated NPM/ALK fusion cDNA in peripheral blood cells of healthy individuals. Br J Haematol 1998; 103: 1138–1144. 7 Voena C, Conte C, Ambrogio C, Boeri EE, Boccalatte F, Mohammed S References et al. The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration. Cancer Res 1 Ma Z, Hill DA, Collins MH, Morris SW, Sumegi J, Zhou M et al. 2007; 67: 4278–4286. Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in 8 Li R, Morris SW. Development of anaplastic lymphoma kinase (ALK) inflammatory myofibroblastic tumor. Genes Chromosomes Cancer small-molecule inhibitors for cancer therapy. Med Res Rev 2008; 2003; 37: 98–105. 28: 372–412. Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu) Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia Leukemia (2010) 24, 1200–1204; doi:10.1038/leu.2010.63; instrumental in BCR-ABL-induced B-ALL progression and poor published online 15 April 2010 clinical outcome.4 To investigate whether impaired IKAROS function can facili- tate BCR-ABL-induced leukemogenesis, we crossed BCR-ABL transgenic mice that exclusively develop B-ALL5 with mice IKAROS is a chromatin-remodeling and sequence-specific carrying an hypomorphic IKZF1 allele (IKL).6 Previous studies transcription factor encoded by the IKZF1 gene that is involved have shown that the IKL allele, generated by the knock-in of Lac in a number of developmental processes in hematopoiesis. In Z into IKZF1 exon 2, produces 5–10% of wt levels of IKAROS particular, IKAROS is essential for the specification of the proteins that lack amino acids encoded by exon 2. Importantly, lymphoid lineages from myeloid/lymphoid multipotent progeni- these mutant proteins were as efficient as wt IKAROS at rescuing tors, is involved in the differentiation of pro-B cells into pre-B abnormal phenotypes from homozygous mutant mice, suggest- cells and, together with the related IKAROS family member ing that the IKL allele is mainly, if not exclusively, a loss of Aiolos, downregulates pre-BCR function (for a review, see Nutt function allele.7,8 Two cohorts of BCR-ABL þ compound and Kee1). Over the past 10 years, reverse transcription–PCR mice were generated that carried either two alleles of wt IKZF1 studies have reported the expression of short IKAROS isoforms (BCR-ABL þ /0;IKþ / þ ), or one wt and one mutant IKZF1 allele in acute lymphoblastic leukemia (ALL) patients at diagnosis, (BCR-ABL þ /0;IKL/ þ ), which were compared for leukemia with higher prevalence in BCR-ABL-associated B-ALL.2 These development. Nontransgenic IK þ / þ and IKL/ þ littermates were short isoforms encode IKAROS proteins that include only two included as controls. In line with previous data,5 BCR-ABL þ /0; out of the four central zinc fingers responsible for their specific IK þ / þ mice developed B-ALL with a median latency of 14,7 binding to DNA while keeping intact the C-terminal zinc fingers weeks (Figure 1a). Strikingly, leukemia onset was considerably involved in their oligomerization with DNA-binding-competent accelerated in BCR-ABL þ /0;IKL/ þ mice (median latency of isoforms of IKAROS and other IKAROS family members. 5.7 weeks; Figure 1a). None of the control groups developed Thus, these short isoforms can function as dominant-negative disease during a 6-month observation period (Figure 1a; data (DN) mutants of wild-type (wt) IKAROS and IKAROS family not shown). Histologically, the leukemias arising from both the members. Recently, comprehensive genome-wide SNP array BCR-ABL þ /0;IKþ / þ and BCR-ABL þ /0;IKL/ þ cohorts were analyses of DNA copy number alterations in ALL showed the similar, with recurrent leukemic cell infiltration of bone marrow, frequent monoallelic deletion of all or part of IKZF1, the latter spleen, lymph nodes, blood and nonhematopoietic tissues situation often linked to the expression of DN IKAROS isoforms including liver and brain (data not shown). Flow cytometry in 475% of pediatric and 490% of adult BCR-ABL B-ALL and analyses identified large leukemic blasts in both cohorts that lymphoid blast crisis chronic myeloid leukemia (CML) patients.3 were B220 þ sIgMÀ with a variable proportion of CD43 þ cells These data suggest that impaired function of IKAROS itself, and in individual leukemias (Figures 1b and c; median value 20% possibly of other members of the IKAROS family, could be and range 1À85% in individual BCR-ABL þ /0;IKþ / þ tumors; Leukemia Letters to the Editor 1201 100 BCR-ABL; IKL/+ 90 +/+ +/+ BCR-ABL; IK 80 BCR ABL; IK 75 L/+ 70 BCR-ABL; IK IKL/+ 60 50 50 40 Survival (%) 25 30 % B220+ CD43+ 20 0 10 0 102030405060 0 Age of mice (weeks) BCR ABL; IK+/+ BCR-ABL; IKL/+ BCR-ABL; IK+/+ BCR-ABL; IKL/+ BCR-ABL; IK+/+ BCR-ABL; IKL/+ 1000 10000 1000 10000 L/L 800 IK Prog. 1318 1396 1414 1443 1455 1466 1469 1000 83.8% 800 1000 77.1% 600 600 100 100 IK1 B220 SSC-H 400 B220 400 IK1* IK2 200 10 10 IK2* 69% 200 62.4% 0 1 0 1 0200 400 600 800 1000 1 10 100 1000 10000 0 200 400 600 800 1000 110 100 1000 10000 FSC-H IgMFSC-H IgM 10000 10000 1000 90.4% 9.18% 1000 81.5% 18.1% Pax5 100 100 B220 B220 10 10 β-Actin 1 1 110 100 1000 10000 1 10 100 1000 10000 CD43 CD43 Figure 1 Impaired IKAROS function accelerates B-ALL onset in BCR-ABL transgenic mice. (a) Kaplan–Meyer survival curves for BCR-ABL þ /0; IK þ / þ , BCR-ABL þ /0;IKL/ þ and IKL/ þ mice. Mice harboring a BCR-ABL construct encoding P190BCR-ABL under control of the metallothionein promoter5 were obtained from the Jackson Laboratory (Charles River Laboratories, L’Arbresle, France), re-derived and backcrossed for eight generations on C57B/6 mice. These mice were crossed to IKL/ þ mice,6 maintained on C57B/6 background and the resulting cohorts of BCR-ABL þ /0; IK þ / þ (n ¼ 101; black line) and BCR-ABL þ /0;IKL/ þ (n ¼ 86; gray line) followed for leukemia development. Cohorts of control IKL/ þ (n ¼ 10; hatched line) and nontransgenic littermates (not shown) were also analyzed. Mice were killed when moribund (mobility weakness or paralysis, lusterless fur, respiratory distress). Survival curves were plotted using the Prism 4 software (Graph Pad Software Inc., San Diego, CA, USA). The nnn P-value (o0.0001 ) for the BCR-ABL þ /0;IKþ / þ and BCR-ABL þ /0;IKL/ þ cohorts was calculated using the log-rank test. (b) Cell-surface analysis of the leukemic cells obtained from the bone marrow of representative BCR-ABL þ /0;IKþ / þ and BCR-ABL þ /0;IKL/ þ cases. Leukemic blasts were gated as FSC/SSC large cells and analyzed for B220, sIgM and CD43 expression, as indicated. The antibodies used were from BD Biosciences (Le Pont De Claix, France): anti-IgM-FITC (R6-60.2), anti-B220-PE-Cy5 (RA3-6B2), anti-CD43-PE (S7). (c) Expression of CD43 in a series of individual leukemias obtained from BCR-ABL þ /0;IKþ / þ and BCR-ABL þ /0;IKL/ þ mice. (d) Western blot analyses of IKAROS, Pax5 and b-actin expression in normal B-cell progenitors (Prog), sorted as B220 þ IgMÀ cells from the bone marrow cells of a pool of 2-month-old control C57B/6 mice and in sorted leukemic blasts (large B220 þ IgMÀ cells) obtained from the bone marrow of BCR-ABL þ /0;IKþ / þ and BCR-ABL þ /0;IKL/ þ mice. The migration positions of the DNA-binding-competent IK1 and IK2 proteins are shown as black arrowheads. An extract obtained from spleen cells from IKL/L mice identify the IK1/2n products (open arrowheads) encoded by the mutant IKL allele.6 IKAROS proteins were identified using an antibody specific of all IKAROS isoforms (E-20; Santa Cruz Biotechnologies, Santa Cruz, CA, USA) and Pax5 was identified using a rat monoclonal antibody to amino acids 154–284 of mouse Pax5 (clone 1H9; a generous gift from Dr M Busslinger, IMP, Vienna, Austria).
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