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Oncogenes Fusion Genes and Tumor Supressor Genes

Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias

Abstract

Overexpression of the c-Myc oncoprotein is observed in a large number of hematopoietic malignancies, and transgenic animal models have revealed a potent role for c-Myc in the generation of leukemias and lymphomas. However, the reason for high c-Myc protein levels in most cases is unknown. We examined whether aberrant protein stabilization could be a mechanism of c-Myc overexpression in leukemia cell lines and in primary bone marrow samples from pediatric acute lymphoblastic leukemia (ALL) patients. We found that c-Myc protein half-life was prolonged in the majority of leukemia cell lines and bone marrow samples tested. There were no mutations in the c-myc gene in any of the leukemia cell lines that could account for increased c-Myc stability. However, abnormal phosphorylation at two conserved sites, Threonine 58 and Serine 62, was observed in leukemia cell lines with stabilized c-Myc. Moreover, stabilized c-Myc from the ALL cell lines showed decreased affinity for glycogen synthase kinase3β, the kinase that phosphorylates c-Myc at Threonine 58 and facilitates its degradation. These findings reveal that deregulation of the c-Myc degradation pathway controlled by Serine 62 and Threonine 58 phosphorylation is a novel mechanism for increased expression of a potent oncoprotein known to be involved in hematopoietic malignancies.

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Acknowledgements

We thank Maria Siri for technical assistance and Peter Kurre and Rachel Dresbeck for their generous help with editing the manuscript. We thank Grover Bagby for providing the JY control cell line. This work was supported by grants from the National Cancer Institute, R01 CA100855 and K01 CA086957 to RCS.

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Correspondence to R C Sears.

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Malempati, S., Tibbitts, D., Cunningham, M. et al. Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias. Leukemia 20, 1572–1581 (2006). https://doi.org/10.1038/sj.leu.2404317

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