Aberrant stabilization of c-Myc protein in some lymphoblastic leukemias

S Malempati, D Tibbitts, M Cunningham, Y Akkari… - Leukemia, 2006 - nature.com
S Malempati, D Tibbitts, M Cunningham, Y Akkari, S Olson, G Fan, RC Sears
Leukemia, 2006nature.com
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 …
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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