Mutations of c-Cbl in myeloid malignancies.

Shulamit Katzav,M Lienhard Schmitz

doi:10.18632/oncotarget.3986

Shulamit Katzav, M Lienhard Schmitz

Open Access

https://doi.org/10.18632/oncotarget.3986

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Abstract

Next generation sequencing has shown the frequent occurrence of point mutations in the ubiquitin E3 ligase c-Cbl in myeloid malignancies. Mouse models revealed a causal contribution of c-Cbl for the onset of such neoplasms. The point mutations typically cluster in the linker region and RING finger domain and affect both alleles by acquired uniparental disomy. The fast progress in the detection of c-Cbl mutations is contrasted by our scarce knowledge on their functional consequences. The c-Cbl protein displays several enzymatic functions by promoting the attachment of differentially composed ubiquitin chains and of the ubiquitin-like protein NEDD8 to its target proteins. In addition, c-Cbl functions as an adapter protein and undergoes phosphorylation-dependent inducible conformation changes. Studies on the impact of c-Cbl mutations on its functions as a dynamic and versatile adapter protein, its interactomes and on its various enzymatic activities are now important to allow the identification of druggable targets within the c-Cbl signaling network.

Highlights

Myeloid malignancies comprise three broad categories: acute myelogenous leukemia (AML) characterized by accumulation of immature myeloid cells in the bone marrow, myelodypastic syndromes (MDS) associated with ineffective hematopoiesis and chronic myeloproliferative disorders (MPDs), usually associated with an increased production of terminally differentiated myeloid cells
multipotent progenitors (MPPs) can differentiate into common myeloid progenitors (CMPs), leading eventually to the generation of the myeloid lineage [2, 4,5,6,7,8]
Mice engineered to express a Casitas B-lineage Lymphoma (c-Cbl) really interesting new gene (RING) domain point mutation (C379A) develop a myeloproliferative disease that progresses to leukemia [41], classifying c-Cbl mutations as driver mutations

Summary

Introduction

Myeloid malignancies comprise three broad categories: acute myelogenous leukemia (AML) characterized by accumulation of immature myeloid cells in the bone marrow, myelodypastic syndromes (MDS) associated with ineffective hematopoiesis and chronic myeloproliferative disorders (MPDs), usually associated with an increased production of terminally differentiated myeloid cells. In addition to these enzymatic activities, the various domains in Cbl proteins enable its function as an adapter by allowing constitutive or phososphorylation-dependent association with a plethora of different proteins [15, 23].

Results

Conclusion