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Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis

Authors :
Gerrit Jan Schuurhuis
Connie R. Jimenez
Anna Wojtuszkiewicz
Johan van Meerloo
Sander R. Piersma
Floortje L. Kessler
Jaco C. Knol
René J. P. Musters
Jacqueline Cloos
Gertjan J.L. Kaspers
Yehuda G. Assaraf
Sonja Zweegman
Gerrit Jansen
Thang V. Pham
Hematology laboratory
CCA - Biomarkers
Medical oncology laboratory
Rheumatology
Physiology
ICaR - Ischemia and repair
Pediatric surgery
Hematology
Source :
Molecular and Cellular Proteomics, 15(4), 1281-1298. American Society for Biochemistry and Molecular Biology Inc., Wojtuszkiewicz, A, Schuurhuis, G J, Kessler, F L, Piersma, S R, Knol, J C, Pham, T V, Jansen, G, Musters, R J P, van Meerloo, J, Assaraf, Y G, Kaspers, G J L, Zweegman, S, Cloos, J & Jimenez, C R 2016, ' Exosomes Secreted by Apoptosis-Resistant Acute Myeloid Leukemia (AML) Blasts Harbor Regulatory Network Proteins Potentially Involved in Antagonism of Apoptosis ', Molecular and Cellular Proteomics, vol. 15, no. 4, pp. 1281-1298 . https://doi.org/10.1074/mcp.M115.052944
Publication Year :
2016

Abstract

Expression of apoptosis-regulating proteins (B-cell CLL/lymphoma 2 - BCL-2, Myeloid Cell Leukemia 1 - MCL-1, BCL-2 like 1 - BCL-X and BCL-2-associated X protein - BAX) in acute myeloid leukemia (AML) blasts at diagnosis is associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. Herein, we further explored this aspect of dynamic apoptosis regulation in AML. First, we showed that the intraindividual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts within the bone marrow of AML patients were highly correlated. The expression values of apoptosis-regulating proteins were far beyond healthy control lymphocytes, which implicates the influence of microenvironmental factors. Second, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p = 0.0067 and p = 1.0, respectively). Using secretome proteomics, we identified novel proteins possibly engaged in apoptosis regulation. Intriguingly, this analysis revealed that major functional protein clusters engaged in global gene regulation, including mRNA splicing, protein translation, and chromatin remodeling, were more abundant (p = 4.01E-06) in secretomes of apoptosis-resistant AML. These findings were confirmed by subsequent extracellular vesicle proteomics. Finally, confocal-microscopy-based colocalization studies show that splicing factors-containing vesicles secreted by high AAI cells are taken up by low AAI cells. The current results constitute the first comprehensive analysis of proteins released by apoptosis-resistant and sensitive primary AML cells. Together, the data point to vesicle-mediated release of global gene regulatory protein clusters as a plausible novel mechanism of induction of apoptosis resistance. Deciphering the modes of communication between apoptosis-resistant blasts may in perspective lead to the discovery of prognostic tools and development of novel therapeutic interventions, aimed at limiting or overcoming therapy resistance.

Details

Language :
English
ISSN :
15359476
Volume :
15
Issue :
4
Database :
OpenAIRE
Journal :
Molecular and Cellular Proteomics
Accession number :
edsair.doi.dedup.....deee28ad6b6a7767e23b5539fde5097b