Cbl and human myeloid neoplasms: the Cbl oncogene comes of age.

Cbl was originally discovered in 1989 as the cellular homolog of the v-Cbl oncogene, the transforming gene of the Cas NS-1 murine retrovirus that causes myeloid leukemia and lymphomas in mice. Cbl is a member of a family of RING finger ubiquitin ligases that negatively regulate signaling by tyrosine kinases and that function as adaptor proteins to regulate signaling positively. Until the past 2 years, there was little evidence that Cbl proteins were involved in human malignancies. Recent publications have shown homozygous mutations in Cbl in human myeloid neoplasms. Although in vitro and animal transformation models suggested that mutant forms of Cbl acted as an oncogene, the cellular role suggested that the protein could serve as a tumor suppressor gene. The recent data begin to reconcile this paradox as the loss of ubiquitin ligase function (the tumor suppressor function) is coupled to the maintenance of the positive signaling function (the oncogene function). These data also provide insight into potential therapeutic approaches to myeloid disorders harboring Cbl mutations.

[1]  R. Kusec,et al.  Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. , 2010, Blood.

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

[3]  Ravi Salgia,et al.  CBL Is Frequently Altered in Lung Cancers: Its Relationship to Mutations in MET and EGFR Tyrosine Kinases , 2010, PloS one.

[4]  M. McDevitt,et al.  Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[6]  R. Aguiar,et al.  Integrity of the CBL gene in mature B-cell malignancies. , 2009, Blood.

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

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

[9]  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.

[10]  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.

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

[12]  Gordon B. Mills,et al.  Derailed endocytosis: an emerging feature of cancer , 2008, Nature Reviews Cancer.

[13]  B. Löwenberg,et al.  Exon 8 splice site mutations in the gene encoding the E3-ligase CBL are associated with core binding factor acute myeloid leukemias , 2008, Haematologica.

[14]  P. Aplan,et al.  Leukemic transformation in mice expressing a NUP98-HOXD13 transgene is accompanied by spontaneous mutations in Nras, Kras, and Cbl. , 2008, Blood.

[15]  M. Caligiuri,et al.  Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. , 2007, Blood.

[16]  Chunaram Choudhary,et al.  Flt3-dependent transformation by inactivating c-Cbl mutations in AML. , 2007, Blood.

[17]  Howard Riezman,et al.  Proteasome-Independent Functions of Ubiquitin in Endocytosis and Signaling , 2007, Science.

[18]  M. Nau,et al.  Regulating the regulator: negative regulation of Cbl ubiquitin ligases. , 2006, Trends in biochemical sciences.

[19]  W. Langdon,et al.  Loss of c‐Cbl RING finger function results in high‐intensity TCR signaling and thymic deletion , 2005, The EMBO journal.

[20]  S. Anderson,et al.  Regulation of Ubiquitin Protein Ligase Activity in c-Cbl by Phosphorylation-induced Conformational Change and Constitutive Activation by Tyrosine to Glutamate Point Mutations* , 2004, Journal of Biological Chemistry.

[21]  S. Fang,et al.  Ubiquitin-proteasome system , 2004, Cellular and Molecular Life Sciences CMLS.

[22]  Morag Park,et al.  Escape from Cbl-mediated downregulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases. , 2003, Cancer cell.

[23]  E. Ujack,et al.  Isolation and characterization of a novel, transforming allele of the c-Cbl proto-oncogene from a murine macrophage cell line , 2002, Oncogene.

[24]  T. Tamura,et al.  c-Cbl Associates Directly with the C-terminal Tail of the Receptor for the Macrophage Colony-stimulating Factor, c-Fms, and Down-modulates This Receptor but Not the Viral Oncogene v-Fms* , 2002, The Journal of Biological Chemistry.

[25]  F. Walker,et al.  RING finger mutations that abolish c-Cbl-directed polyubiquitination and downregulation of the EGF receptor are insufficient for cell transformation. , 2001, Molecular cell.

[26]  A Ciechanover,et al.  Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. , 1999, Molecular cell.

[27]  J. Brugge,et al.  Controlled Dimerization of ErbB Receptors Provides Evidence for Differential Signaling by Homo- and Heterodimers , 1999, Molecular and Cellular Biology.

[28]  W. Langdon,et al.  Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl , 1997, Oncogene.

[29]  W. Langdon,et al.  EGF receptor binding and transformation by v-cbl is ablated by the introduction of a loss-of-function mutation from the Caenorhabditis elegans sli-1 gene , 1997, Oncogene.

[30]  J. Whittaker,et al.  FMS mutations in patients following cytotoxic therapy for lymphoma. , 1995, Leukemia research.

[31]  W. Langdon,et al.  Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene. , 1994, The EMBO journal.

[32]  M. Worwood,et al.  FMS mutations in myelodysplastic, leukemic, and normal subjects. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

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