Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation.

Yoshira M Ayala-Marin,Alice H Grant,Robert A Kirken,Georgialina Rodriguez

doi:10.3390/ijms222212210

Yoshira M Ayala-Marin, Alice H Grant + Show 2 more

Open Access

https://doi.org/10.3390/ijms222212210

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Abstract

Compared to other ethnicities, Hispanic children incur the highest rates of leukemia, and most cases are diagnosed as Acute Lymphoblastic Leukemia (ALL). Despite improved treatment and survival for ALL, disproportionate health outcomes in Hispanics persist. Thus, it is essential to identify oncogenic mutations within this demographic to aid in the development of new strategies to diagnose and treat ALL. Using whole-exome sequencing, five single nucleotide polymorphisms within mitogen-activated protein kinase 3 (MAP2K3) were identified in an ALL cancer patient library from the U.S./Mexico border. MAP2K3 R26T and P11T are located near the substrate-binding site, while R65L and R67W localized to the kinase domain. Truncated-MAP2K3 mutant Q73* was also identified. Transfection in HEK293 cells showed that the quadruple-MEK3 mutant (4M-MEK3) impacted protein stability, inducing degradation and reducing expression. The expression of 4M-MEK3 could be rescued by cysteine/serine protease inhibition, and proteasomal degradation of truncated-MEK3 occurred in a ubiquitin-independent manner. MEK3 mutants displayed reduced auto-phosphorylation and enzymatic activity, as seen by decreases in p38 phosphorylation. Furthermore, uncoupling of the MEK3/p38 signaling pathway resulted in less suppressive activity on HEK293 cell viability. Thus, disruption of MEK3 activation may promote proliferative signals in ALL. These findings suggest that MEK3 represents a potential therapeutic target for treating ALL.

Highlights

Acute lymphocytic leukemia (ALL) is a blood and bone marrow cancer that primarily affects children [1]
We investigated the role of four mitogen-activated protein kinase 3 (MEK3) mutations found within an ALL cohort, including R65L and R67W localized near the ATP binding site and P11T and R26T residing in the amino-terminal domain [24]
Inhibition of p38 by degradation of MEK3 may render this pathway inactive and contribute to aberrant growth and survival signals in ALL. These findings suggest that MEK3 activation represents a potential therapeutic target for treating ALL

Summary

Introduction

Acute lymphocytic leukemia (ALL) is a blood and bone marrow cancer that primarily affects children [1]. It is responsible for causing more deaths than any other childhood cancer, and its incidence is highest among Hispanics [2,3,4]. Less than 1% of biorepository specimens and 2% of samples in genome-wide association studies are derived from Hispanics [5]. This underrepresentation might reflect the disproportionate health outcomes observed in some minority groups [6]. Some patients experience refractory or ALL relapse, where the 5-year free survival rate falls by between 15 and 50% [8]. Understanding the molecular mechanisms responsible for driving ALL in this demographic is essential to developing new therapeutic strategies [9]

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