DAP Kinase-Related Apoptosis-Inducing Protein Kinase 2 (DRAK2) Is a Key Regulator and Molecular Marker in Chronic Lymphocytic Leukemia.

Katarzyna Szoltysek,Peixun Zhou,Anna Walaszczyk,Vikki Rand,Christine J Harrison,Carmela Ciardullo,Jeyanthy Eswaran,Andy Hall,Scott Marshall,Elaine Willmore,Meera Soundararajan

doi:10.3390/ijms21207663

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and it is characterized by a marked degree of clinical heterogeneity. An impaired balance between pro- and anti-apoptotic stimuli determines chemorefractoriness and outcome. The low proliferation rate of CLL cells indicates that one of the primary mechanisms involved in disease development may be an apoptotic failure. Here, we study the clinical and functional significance of DRAK2, a novel stress response kinase that plays a critical role in apoptosis, T-cell biology, and B-cell activation in CLL. We have analyzed CLL patient samples and showed that low expression levels of DRAK2 were significantly associated with unfavorable outcome in our CLL cohort. DRAK2 expression levels showed a positive correlation with the expression of DAPK1, and TGFBR1. Consistent with clinical data, the downregulation of DRAK2 in MEC-1 CLL cells strongly increased cell viability and proliferation. Further, our transcriptome data from MEC-1 cells highlighted MAPK, NF-κB, and Akt and as critical signaling hubs upon DRAK2 knockdown. Taken together, our results indicate DRAK2 as a novel marker of CLL survival that plays key regulatory roles in CLL prognosis.

Highlights

Chronic lymphocytic leukemia (CLL) represents the most common adult leukemia in the western world, accounting for ~40% of adult leukemia [1,2]
This study showed a positive correlation between DRAK2 and DAPK1, DAPK1 expression was not an indicator of prognosis, nor was it associated with other clinical markers, as this study showed a positive correlation between DRAK2 and DAPK1, DAPK1 expression was not an indicator of prognosis, nor was it associated with other clinical markers, as reported previously
While it is possible that the DAPK1 promoter methylation mark may play a role in hereditary CLL, our study has shown that total RNA expression of DAPK1 is not a prognostic marker in sporadic, randomly selected CLL

Summary

Introduction

Chronic lymphocytic leukemia (CLL) represents the most common adult leukemia in the western world, accounting for ~40% of adult leukemia [1,2]. It is a malignancy of mature clonal B-lymphocytes that accumulate in the blood, bone marrow, and lymphoid tissues [2,3]. Unlike other B-cell malignancies, CLL is not usually associated with chromosomal translocations Cytogenetic abnormalities, such as deletions of 13q14, 11q22-q23, and 17p13, trisomy 12 [6], and high-level expression of serum markers (CD38, Zeta-chain-associated protein kinase 70 (ZAP-70)) are critical predictors of disease progression and survival [7,8,9,10]. 15% of CLL show aberrations in a few frequently affected chromosomal regions, including ATM and TP53 genes, which are correlated with disease progression and overall survival [4,12]

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Discussion

Conclusion