Activating CBL mutations are associated with a distinct MDS/MPN phenotype
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Activating point mutations in CBL have recently been identified in diverse subtypes of myeloid neoplasms. Because detailed clinical and hematological characteristics of CBL-mutated cases is lacking, we screened 156 BCR-ABL and JAK2 V617F negative patients with myeloproliferative neoplasms (MPN) and overlap syndromes between myelodysplastic syndrome (MDS) and MPN (MPS/MPN) for mutations in exons 8 and 9 of CBL by denaturing high-performance liquid chromatography and direct sequencing. CBL mutations were identified in 16/156 patients (10 %), of which five also carried mutations in EZH2 (n = 3) and TET2 (n = 2). Comprehensive clinical and hematological characteristics were available from 13/16 patients (81 %). In addition to splenomegaly (77 %), striking common hematological features were CML-like left-shifted leukocytosis (85 %) with monocytosis (85 %), anemia (100 %), and thrombocytopenia (62 %). Thrombocytosis was not observed in any patient. Relevant bone marrow features (n = 12) included hypercellularity (92 %) with marked granulopoiesis (92 %), nonclustered microlobulated megakaryocytes (83 %), and marrow fibrosis (83 %). Nine deaths (progression to secondary acute myeloid leukemia/blast phase, n = 7; cytopenia complications, n = 2) were recorded. Three-year survival rate was 27 %, possibly indicating poor prognosis of CBL mutated MDS/MPN patients.
KeywordsCBL Point mutations MDS/MPN Clinical phenotype
This work was supported by the “Deutsche José Carreras Leukämie-Stiftung e.V.” (AR R09/29f), Germany. The authors would like to thank Iris Palme and Carolin Hölting, Universitätsmedizin Mannheim, for technical support.
Authorship and disclosure
JS, TE, PE, JR, NCPC, and MM performed the laboratory work for the study; AH, AR, SS, TH, GM, NCPC, and WKH provided patient material; PS reviewed the bone marrow biopsies; JS and AR wrote the paper; AH, NCPC, and WKH revised the manuscript.
- 1.Grand FH, Hidalgo-Curtis CE, Ernst T, Zoi K, Zoi C, McGuire C, Kreil S, Jones A, Score J, Metzgeroth G, Oscier D, Hall A, Brandts C, Serve H, Reiter A, Chase AJ, Cross NC (2009) Frequent cbl mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113:6182–6192PubMedCrossRefGoogle Scholar
- 2.Makishima H, Cazzolli H, Szpurka H, Dunbar A, Tiu R, Huh J, Muramatsu H, O'Keefe C, Hsi E, Paquette RL, Kojima S, List AF, Sekeres MA, McDevitt MA, Maciejewski JP (2009) Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol 27:6109–6116PubMedCrossRefGoogle Scholar
- 3.Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A, Drexler HG, Duncombe A, Cervantes F, Oscier D, Boultwood J, Grand FH, Cross NC (2010) Inactivating mutations of the histone methyltransferase gene ezh2 in myeloid disorders. Nat Genet 42:722–726Google Scholar
- 4.Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B, Dicker F, Schnittger S, Dugas M, Kern W, Haferlach C, Haferlach T (2010) Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8 % of chronic myelomonocytic leukemia by detecting frequent alterations in tet2, cbl, ras, and runx1. J Clin Oncol 28:3858–3865PubMedCrossRefGoogle Scholar
- 5.Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Yamagata T, Takita J, Gotoh N, Nakazaki K, Kawamata N, Onodera M, Nobuyoshi M, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S (2009) Gain-of-function of mutated c-cbl tumour suppressor in myeloid neoplasms. Nature 460:904–908PubMedCrossRefGoogle Scholar
- 6.Tefferi A, Vainchenker W (2011) Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 29:573–582Google Scholar
- 7.Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon KM, Niemeyer CM (2009) Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114(9):1859–1863PubMedCrossRefGoogle Scholar
- 8.Loh ML (2011) Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol 152:677–687Google Scholar
- 9.Dunbar AJ, Gondek LP, O'Keefe CL, Makishima H, Rataul MS, Szpurka H, Sekeres MA, Wang XF, McDevitt MA, Maciejewski JP (2008) 250 k Single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-cbl, in myeloid malignancies. Cancer Res 68:10349–10357PubMedCrossRefGoogle Scholar
- 10.Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, Tadrist Z, Olschwang S, Vey N, Birnbaum D, Gelsi-Boyer V, Mozziconacci MJ (2010) Combined mutations of asxl1, cbl, flt3, idh1, idh2, jak2, kras, npm1, nras, runx1, tet2 and wt1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer 10:401Google Scholar
- 11.Reindl C, Quentmeier H, Petropoulos K, Greif PA, Benthaus T, Argiropoulos B, Mellert G, Vempati S, Duyster J, Buske C, Bohlander SK, Humphries KR, Hiddemann W, Spiekermann K (2009) Cbl exon 8/9 mutants activate the flt3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res 15:2238–2247PubMedCrossRefGoogle Scholar
- 12.Abbas S, Rotmans G, Lowenberg B, Valk PJ (2008) Exon 8 splice site mutations in the gene encoding the e3-ligase cbl are associated with core binding factor acute myeloid leukemias. Haematologica 93:1595–1597Google Scholar
- 17.Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A (2005) European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90:1128–1132Google Scholar
- 18.Muramatsu H, Makishima H, Jankowska AM, Cazzolli H, O'Keefe C, Yoshida N, Xu Y, Nishio N, Hama A, Yagasaki H, Takahashi Y, Kato K, Manabe A, Kojima S, Maciejewski JP (2009) Mutations of e3 ubiquitin ligase cbl family members but not tet2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood 27(36):6109–6116Google Scholar
- 22.Cambier N, Renneville A, Cazaentre T, Soenen V, Cossement C, Giraudier S, Grardel N, Lai JL, Rose C, Preudhomme C (2008) Jak2v617f-positive polycythemia vera and philadelphia chromosome-positive chronic myeloid leukemia: one patient with two distinct myeloproliferative disorders. Leukemia 22:1454–1455PubMedCrossRefGoogle Scholar
- 25.Kao HW, Sanada M, Liang DC, Lai CL, Lee EH, Kuo MC, Lin TL, Shih YS, Wu JH, Huang CF, Ogawa S, Shih LY (2011) A high occurrence of acquisition and/or expansion of c-cbl mutant clones in the progression of high-risk myelodysplastic syndrome to acute myeloid leukemia. Neoplasia 13:1035–1042PubMedGoogle Scholar