Oncotarget

Research Papers:

Decreased calpain activity in chronic myeloid leukemia impairs apoptosis by increasing survivin in myeloid progenitors and xiap1 in differentiating granulocytes

Weiqi Huang, Ling Bei, Elizabeth E. Hjort and Elizabeth A. Eklund _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:50629-50641. https://doi.org/10.18632/oncotarget.16884

Metrics: PDF 536 views  |   HTML 1359 views  |   ?  


Abstract

Weiqi Huang1,2, Ling Bei1,2, Elizabeth E. Hjort1,2 and Elizabeth A. Eklund1,2

1The Feinberg School at Northwestern University, Chicago, IL, USA

2Jesse Brown VA Medical Center, Chicago, IL, USA

Correspondence to:

Elizabeth A. Eklund, email: e-eklund@northwestern.edu

Keywords: leukemia, Calpain, apoptosis, myeloid, survivin

Received: November 10, 2016     Accepted: March 27, 2017     Published: April 06, 2017

ABSTRACT

Chronic Myeloid Leukemia (CML) is characterized by translocations between chromosomes 9 and 22, resulting in expression of Bcr-abl oncogenes. Although the clinical course of CML was revolutionized by development of Bcr-abl-directed tyrosine kinase inhibitors (TKIs), CML is not cured by these agents. Specifically, the majority of subjects relapsed in clinical trials attempting TKI discontinuation, suggesting persistence of leukemia stem cells (LSCs) even in molecular remission. Identifying mechanisms of CML-LSC persistence may suggest rationale therapeutic targets to augment TKI efficacy and lead to cure. Apoptosis resistance is one proposed mechanism. In prior studies, we identified increased expression of Growth Arrest Specific 2 (Gas2; a Calpain inhibitor) in Bcr-abl+ bone marrow progenitor cells. A number of previously described Calpain substrates might influence apoptosis in CML, including βcatenin and the X-linked Inhibitor of Apoptosis Protein 1 (Xiap1). We previously found Gas2/Calpain dependent stabilization of βcatenin in CML, and increased expression of βcatenin target genes, including Survivin (also an IAP). In the current work, we investigate contributions of Survivin and Xiap1 to Fas-resistance in Bcr-abl+ bone marrow cells. Inhibitors of these proteins are currently in clinical trials for other malignancies, but a role for either IAP in CML-LSC persistence is unknown.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 16884