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Gain of CBL-Interacting Protein, a Possible Alternative to CBL Mutations in Myeloid Malignancies

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Gain of CBL-Interacting Protein, a Possible Alternative to CBL Mutations in Myeloid Malignancies Letters to the Editor 1539 Gain of CBL-interacting protein, a possible alternative to CBL mutations in myeloid malignancies Leukemia (2010) 24, 1539–1541; doi:10.1038/leu.2010.135; Therapeutic abstention was decided. Ten months later, published online 17 June 2010 the patient died of meningitis. The HD-0176 genome did not have any other alteration except a gain of the AHR gene at 7p21, the role of which is unknown; it is noticeable, however, Alterations of several genes have a role in leukemogenesis. that AHR can act as CBL, as an E3 ubiquitin ligase,8 and that These genes may have distinct functions or may be involved in both AHR and CBL participate in the JUN and P38 kinase the same complexes or pathways. Several recent studies have pathways. shown that the CBL gene, located in chromosome region In the same panel we searched for mutations in exons 8 and 11q23.3, is mutated in chronic myeloid diseases.1–3 CBL 9ofCBL. DNA sequencing was done as described.7 Five encodes an E3 ubiquitin ligase that attenuates the proliferative MDS cases, all RAEB2, were mutated in CBL (7.8%): signal transduced by tyrosine kinase receptors such as FLT3 and p.Glu366Lys, p.Tyr368X, p.Leu380Pro, p.Lys381Arg and KIT by enhancing their ubiquitination, downregulation, and p.Pro417Leu (Supplementary Table 1). One substitution lysosomal degradation. CBL mutations modify the protein occurred in the case with trisomy 11 (HD-0264). Mutations activity4 and lead to an increased and/or prolonged signal. of CBL, including two homozygous, were found in five The two other members of the CBL family, CBLB and CBLC, are CMML cases (B10%, four in MP forms: p.Tyr317His, also mutated in few cases of chronic myeloid diseases.3 p.Cys396Tyr, p.Cys404Tyr and p.Phe418Ser; one in MD form: Mutations of CBL can be heterozygous or homozygous. Patients p.Cys404Tyr) (Supplementary Table 2). The results are summar- with homozygous mutations fare worse than patients with ized in Table 1. heterozygous ones.3 Most often homozygosity results from SH3KBP1 (SH3-domain kinase binding protein 1), also acquired somatic uniparental disomy of chromosome arm 11q called CIN85 (CBL-interacting protein of 85 kDa), codes for (11qUPD), which is detected by genome analyses using a cytoplasmic adaptor molecule that interacts and cooperates single-nucleotide polymorphism arrays. Malignant genomes with CBL to regulate signaling.9–11 RCMD HD-0747 and can also be studied by array-comparative genomic hybridization MP-CMML HD-0176, the two cases with Xp22 SH3KBP1 gain, (aCGH). occurred in males and displayed a normal karyotype. They were We used this latter technique to study 63 cases of not mutated in CBL exons 8 and 9. They were not mutated myelodysplastic (MD) syndromes (MDSs) and 53 cases either in ASXL1, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, of chronic myelomonocytic leukemias (CMMLs). According to RUNX1, TET2 and WT1 genes (not shown). As determined by the WHO classification,5 the MDS panel comprised 5 cases of aCGH, the SH3KBP1 gain was limited to an additional copy. refractory anemia (RA), 13 cases of RA with ring sideroblasts, This duplication and the CBL UPD11q suggest that limited 6 cases of refractory cytopenia with multilineage dysplasia variations of the pathway are sufficient to induce an effect on (RCMD), 16 cases of RA with excess of blasts type 1 (RAEB1), signaling. Mutations of CBL have an effect on cell proliferation.4 19 cases of RA with excess of blasts type 2 (RAEB2) and 4 cases SH3KBP1/CIN85 cooperates with CBL in the downregulation of MDS-unclassified. The 53 CMML panel comprised 25 MD of signaling receptors.10 Because of UPD11q two copies of the forms (leucocytosis count o13 Â 109/l) and 28 myeloprolifera- mutated CBL gene are often present in the malignant clone. In a tive (MP) forms (leucocytosis count 413 Â 109/l).6 All patients similar way, it could be possible that the SH3KBP1 duplicated signed an informed consent and the study was approved by gene is mutated. We have looked in our Affymetrix microarray our ethics committee. aCGH was done with high-density data for the expression of SH3KBP1 in HD-0176, for which we oligonucleotide microarrays (Hu-244A, Agilent Technologies, had mRNA. The level of expression was not overtly modified as Massy, France), as described previously.6 compared with normal bone marrow or other MDS/CMML Two-thirds of the 63 MDS cases showed no copy number samples. alterations (CNAs) (that is, neither gain nor loss) (Supplementary In summary, we have found two examples of alteration of a Table 1). Few cases had a single small CNA such as loss at 4q24 gene encoding a CBL interactor. This alteration may play a role (TET2), loss at 2p11 and gain at Xp22 (Figure 1). Gain at Xp22, similar to that of CBL mutations in chronic myeloid diseases. found in RCMD HD-0747, contained the SH3KBP1 gene (SH3- Although the anomaly is rare (1.7% in our series), it is not domain kinase binding protein; chrX: 19 463 441–19 815 640). insignificant. First, the number of CNAs was globally low; in Patient HD-0747, a 77-year-old man, has been followed up comparison we found only two deletions of TET2 and since 2003 for RA in therapeutic abstention. In June 2009, one deletion of ASXL1 in the same panel. Second, SH3KBP1 a bone marrow aspiration showed evolution to RCMD. The gain increases by about 20% the cases with alteration of the sample analyzed was taken at this period. Patient HD-0747 CBL pathway (2 cases out of 116 tested; to be compared with is currently maintained in partial hematological response 10 mutated CBL). Third, it shows specificity, as we have not under high doses of erythropoietin. aCGH did not show any detected such gain in 300 breast or colon cancers (not shown). other CNA in the HD-0747 genome. This emphasizes the importance of CBL-associated deregulation Out of the 53 CMMLs, 37 cases (68%) showed no CNA of signaling in chronic myeloid diseases and constitutes (some of these cases have been reported previously7) (Supple- an incentive to look for alterations in other members of the mentary Table 2). Ten cases had a single or few small CBL/CIN85 pathway.12 In that respect we found a gain of the CNAs, including loss of NF1, RB1 or TET2. One of these, gene encoding MAP3K4, an interactor of CIN85,13 in a RAEB1 HD-0176, showed a gain of SH3KBP1. Patient HD-0176 was a with complex aCGH profile, and a gain of the gene encoding 46-year-old man diagnosed with CMML1 in December 2006. the CBL interactor ARHGEF7/bPIX in an RCMD in a reported Leukemia Letters to the Editor 1540 Figure 1 Chromosome X aCGH profiles showing SH3KBP1 gain. (a) RCMD HD-0747 shows a gain of one copy of the SH3KBP1 gene (arrows). Case HD-0637 represents the baseline profile and case HD-0411 (female) a profile corresponding to two chromosomes X. (b) CMML HD-0176 shows one copy gain of SH3KBP1. CMML HD-0366 represents the baseline profile and HD-0367 a profile corresponding to two chromosomes X. Table 1 Summary of results Acknowledgements MDS CMML Total This work was supported by Institut Paoli-Calmettes, Inserm, and grants from the Association pour la Recherche contre le Cancer Number of cases studied 63 53 116 (no. 4992). aCGH CNA 40 (63.5%) 37 (69.8%) 77 (66.4%) SH3KBP1/CIN85 gain 1 (1.6%) 1 (1.9%) 2 (1.7%) J Ade´laı¨de1, V Gelsi-Boyer1,2,3, J Rocquain1, N Carbuccia1, CBL mutation 5 (7.9%) 5 (9.4%) 10 (8.6 %) DJ Birnbaum1, P Finetti1, F Bertucci1,3, MJ Mozziconacci1,2, Total alterations of pathway 6 (9.5%) 6 (11.3%) 12 (10.3%) N Vey3,4, D Birnbaum1 and M Chaffanet1 1 Abbreviations: aCGH, array-comparative genomic hybridization; Centre de Recherche en Cance´rologie de Marseille, CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic Laboratoire d’Oncologie Mole´culaire, UMR891 Inserm, syndrome. Institut Paoli-Calmettes, Marseille, France; 2De´partement de BioPathologie, Institut Paoli-Calmettes, Marseille, France; 3Faculte´ de Me´decine, Universite´ de la Me´diterrane´e, 14 Marseille, France and study. Whether other E3 ubiquitin ligases (for example, AHR 4 or SCF components) may have a role in these diseases also De´partement d’He´matologie, Institut Paoli-Calmettes, needs to be investigated. Marseille, France E-mail: [email protected] References Conflict of interest 1 Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS, The authors declare no conflict of interest. Szpurka H et al. 250K single nucleotide polymorphism array Leukemia Letters to the Editor 1541 karyotyping identifies acquired uniparental disomy and homo- frequent alterations of RAS and RUNX1 genes. BMC Cancer 2008; zygous mutations, including novel missense substitutions of c-Cbl, 8: 299–314. in myeloid malignancies. Cancer Res 2008; 68: 10340–10357. 8 Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H et al. 2 Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. et al. Frequent CBL mutations associated with 11q acquired Nature 2007; 444: 562–566. uniparental disomy in myeloproliferative neoplasms. Blood 2009; 9 Take H, Watanabe S, Takeda K, Yu ZX, Iwata N, Kajigaya S. 113: 6182–6192. Cloning and characterization of a novel adaptor protein, CIN85, 3 Makishima H, Cazzolli H, Szpurka H, Dunbar A, Tiu R, Huh J et al. that interacts with c-Cbl. Biochem Biophys Res Commun 2000; Mutations of E3 ligase Cbl family members constitute a novel 268: 321–328.
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