Activating CBL mutations are associated with a distinct MDS/MPN phenotype

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.

[1]  A. Tsygankov,et al.  Beyond the RING: CBL proteins as multivalent adapters , 2001, Oncogene.

[2]  R. Arceci Mutations of E3 Ubiquitin Ligase Cbl Family Members Constitute a Novel Common Pathogenic Lesion in Myeloid Malignancies , 2010 .

[3]  Daniel Birnbaum,et al.  Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias , 2010, BMC Cancer.

[4]  Ivan Dikic,et al.  The Cbl interactome and its functions , 2005, Nature Reviews Molecular Cell Biology.

[5]  H. Drexler,et al.  Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders , 2010, Nature Genetics.

[6]  J. Melo,et al.  An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. , 1994, Leukemia.

[7]  Ayalew Tefferi,et al.  Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  A. Tsygankov,et al.  The Cbl family proteins: Ring leaders in regulation of cell signaling , 2006, Journal of cellular physiology.

[9]  C. Preudhomme,et al.  JAK2V617F-positive polycythemia vera and Philadelphia chromosome-positive chronic myeloid leukemia: one patient with two distinct myeloproliferative disorders , 2008, Leukemia.

[10]  J. D. van der Walt,et al.  European consensus on grading bone marrow fibrosis and assessment of cellularity. , 2005, Haematologica.

[11]  A. Hall,et al.  Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. , 2008, Blood.

[12]  村松 秀城 Mutations of E3 ubiquitin ligase Cbl family members but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia , 2010 .

[13]  M. McDevitt,et al.  250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. , 2008, Cancer research.

[14]  A. Jankowska,et al.  Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. , 2010, Blood.

[15]  U. Hellman,et al.  Alix Facilitates the Interaction between c-Cbl and Platelet-derived Growth Factor β-Receptor and Thereby Modulates Receptor Down-regulation* , 2006, Journal of Biological Chemistry.

[16]  S. Ogawa,et al.  Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms , 2009, Nature.

[17]  M. Loh,et al.  Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia , 2011, British journal of haematology.

[18]  A. Kohlmann,et al.  Gene expression profiling for diagnosis and therapy in acute leukaemia and other haematologic malignancies. , 2010, Cancer treatment reviews.

[19]  M. Loh,et al.  Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. , 2009, Blood.

[20]  Martin C. Müller,et al.  JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia. , 2007, The Lancet. Oncology.

[21]  Tung-Liang Lin,et al.  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. , 2011, Neoplasia.

[22]  Martin Dugas,et al.  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. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Xuejun Jiang,et al.  Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. , 2006, Molecular cell.

[24]  J. Duyster,et al.  E3 ligase-defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease. , 2009, Blood.

[25]  W. Hiddemann,et al.  CBL Exon 8/9 Mutants Activate the FLT3 Pathway and Cluster in Core Binding Factor/11q Deletion Acute Myeloid Leukemia/Myelodysplastic Syndrome Subtypes , 2009, Clinical Cancer Research.