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CBL
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Interpretation 48
Tier 2
CBL
Variants
CBL any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Myelodysplastic Syndrome
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

CBL (casitas-B-lineage lymphoma) gene mutations have been identified in approximately 15% of chronic myelomonocytic leukemia, 15% of juvenile myelomonocytic leukemia, 15% of secondary AML(from MDS or MDS/MPN overlap syndrome) and rare or absent in polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia and MDS. Also, CBL mutations are found in only 1% of de novo acute leukemias and tend to be associated with core binding factor acute myeloid leukemia (AML) among AML cases. CBL is a Ras pathway gene and has been associated with hereditary myeloid disorders. CBL ubiquitinylates and degrades activated receptor and non-receptor tyrosine kinases via the E3-ligase activity of its RING domain. CBL also acts as an adaptor for downstream cell signal transduction, via its tyrosine kinase binding domain. Most variants of the CBL protein are missense substitutions in the zinc binding RING domain (amino acids 366-420) (exons 8-9) that abrogate CBL ubiquitin ligase activity but retain other functions. Pathogenic mutations are believed to be oncogenic by a variety of potential mechanisms including increased Ras pathway activation, aberrant phosphoSTAT5 and/or increased KIT expression in different cellular contexts. Occasionally, two CBL mutations may be present or CBL mutations may be associated with uniparental disomy. In addition, CBL mutations may occur together with mutations in other genes ( RUNX1, ASXL1, TET2 or EZH2 ). According to some studies, mutations of CBL may be associated with reduced overall survival in MDS.

Citations
  1. Schwaab J, et al. Activating CBL mutations are associated with a distinct MDS/MPN phenotype. Ann Hematol 2012;91(11):1713-20
  2. Ibanez M, et al. Rapid screening of ASXL1, IDH1, IDH2, and c-CBL mutations in de novo acute myeloid leukemia by high-resolution melting. J Mol Diagn 2012;14(6):594-601
  3. Aranaz P, et al. CBL RING finger deletions are common in core-binding factor acute myeloid leukemias. Leuk Lymphoma 2013;54(2):428-31
  4. Schnittger S, et al. Use of CBL exon 8 and 9 mutations in diagnosis of myeloproliferative neoplasms and myelodysplastic/myeloproliferative disorders: an analysis of 636 cases. Haematologica 2012;97(12):1890-4
  5. Perez B, et al. Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. Br J Haematol 2010;151(5):460-8
  6. Makishima H, et al. Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. J Clin Oncol 2009;27(36):6109-16
  7. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes (Version 1.2019).
Last updated: 2019-08-28 14:54:01 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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