Oncotarget

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Identification of heat shock protein 32 (Hsp32) as a novel target in acute lymphoblastic leukemia

Sabine Cerny-Reiterer, Renata A. Meyer, Harald Herrmann, Barbara Peter, Karoline V. Gleixner, Gabriele Stefanzl, Emir Hadzijusufovic, Winfried F. Pickl, Wolfgang R. Sperr, Junia V. Melo, Hiroshi Maeda, Ulrich Jäger and Peter Valent _

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Oncotarget. 2014; 5:1198-1211. https://doi.org/10.18632/oncotarget.1805

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Abstract

Sabine Cerny-Reiterer1,2, Renata A. Meyer2, Harald Herrmann1,2, Barbara Peter1,2, Karoline V. Gleixner2, Gabriele Stefanzl2, Emir Hadzijusufovic1,2,3, Winfried F. Pickl4, Wolfgang R. Sperr2, Junia V. Melo5, Hiroshi Maeda6, Ulrich Jäger2, Peter Valent1,2

1 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;

2 Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria;

3 Department of Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria;

4 Institute of Immunology, Medical University of Vienna, Austria;

5 Department of Haematology Centre for Cancer Biology, Adelaide, Australia; and

6 Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto and BioDynamics, Research Laboratory, Kumamoto, Japan

Correspondence:

Peter Valent, email:

Keywords: ALL, imatinib-resistance, Hsp32, HO-1, targeting

Received: February 13, 2014 Accepted: March 2, 2014 Published: March 4, 2014

Abstract

Heat shock proteins (Hsp) are increasingly employed as therapeutic targets in oncology. We have shown that Hsp32, also known as heme oxygenase-1 (HO-1), serves as survival factor and potential target in Ph+ chronic myeloid leukemia. We here report that primary cells and cell lines derived from patients with acute lymphoblastic leukemia (ALL) express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. Highly enriched CD34+/CD38− ALL stem cells also expressed Hsp32. Two Hsp32-targeting drugs, pegylated zinc protoporphyrine (PEG-ZnPP) and styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP), induced apoptosis and growth arrest in the BCR/ABL1+ cell lines, in Ph− lymphoblastic cell lines and in primary Ph+ and Ph− ALL cells. The effects of PEG-ZnPP and SMA-ZnPP on growth of leukemic cells were dose-dependent. In Ph+ ALL, major growth-inhibitory effects of the Hsp32-targeting drugs were observed in imatinib-sensitive and imatinib-resistant cells. Hsp32-targeting drugs were found to synergize with imatinib, nilotinib, and bendamustine in producing growth inhibition and apoptosis in Ph+ ALL cells. A siRNA against Hsp32 was found to inhibit growth and survival of ALL cells and to synergize with imatinib in suppressing the growth of ALL cells. In conclusion, Hsp32 is an essential survival factor and potential new target in ALL.


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