Acute lymphoblastic leukemia

The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL

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Abstract

Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert anti-neoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations. Likewise, givinostat killed primary cells, but not their normal hematopoietic counterparts, from patients carrying CRLF2 rearrangements. At low doses, givinostat downregulated the expression of genes belonging to the JAK/STAT pathway and inhibited STAT5 phosphorylation. In vivo, givinostat significantly reduced engraftment of human blasts in patient-derived xenograft models of CRLF2-positive BCP-ALL. Importantly, givinostat killed ruxolitinib-resistant cells and potentiated the effect of current chemotherapy. Thus, givinostat in combination with conventional chemotherapy may represent an effective therapeutic option for these difficult–to-treat subsets of ALL. Lastly, the selective killing of cancer cells by givinostat may allow the design of reduced intensity regimens in CRLF2-rearranged Down syndrome-associated BCP-ALL patients with an overall benefit in terms of both toxicity and related complications.

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Acknowledgements

AM Savino is supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC and FIRC, grant no. 16645) from the parents’ association ‘Insieme ad Andrea si può, ONLUS’ and from the family of Alessandra Aloisi. This study was supported by grants from: Fondazione Tettamanti, Fondazione Città della Speranza, Associazione Italiana Ricerca sul Cancro (AIRC) (to GteK, GC, AB), CARIPARO project of excellence (to GteK), Fondazione Cariplo (to AB, GC and GteK), Beat Leukemia Foundation (to CP) The Israel Science Foundation, Legacy program and the Israeli Health Ministry (to SI) the European Union’s Seventh Framework Program (FP7/2007-2013) under the project European Network for Cancer research in Children and Adolescents (ENCCA, grant agreement HEALTH-F2-2011-261474) (to AB, GC and GteK). We thank Dr Andrea Ballerini for many helpful discussions and Riccardo Milan for graphic support.

Author contributions

AMS, JS, LT, MV, GF, MB, CB and CP performed the experiments; AMS, JS, LT and CP analyzed the data; AMS, LT, KD, CP and GC wrote the manuscript; GF, KD, GG, SI, LHM, GPN, AB and GTK supervised the research; CP and GC designed the study and supervised the research.

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Correspondence to A Biondi or G Cazzaniga.

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Competing interests

GF is an employee of Italfarmaco SpA. GPN is a paid consultant for Fluidigm, the manufacturer that produced some of the reagents and instrumentation used in this manuscript. The remaining authors declare no conflict of interest.

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Savino, A., Sarno, J., Trentin, L. et al. The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL. Leukemia 31, 2365–2375 (2017) doi:10.1038/leu.2017.93

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