Sep 5, 2015 - fedratinib, momelotinib, or pacritinib alone or in combination with daunrobucin, vincristine or dexamethasone (synergistic effect). The efficacy of ...
9/5/2015
Abstract 4369: Rearrangements of the erythropoietin receptor are recurrent in Phlike acute lymphoblastic leukemia and are sensitive to Jak2 inhibition
Cancer Research cancerres.aacrjournals.org doi: 10.1158/15387445.AM20154369 Cancer Res August 1, 2015 75; 4369
Abstract 4369: Rearrangements of the erythropoietin receptor are recurrent in Phlike acute lymphoblastic leukemia and are sensitive to Jak2 inhibition Ilaria Iacobucci 1, Kathryn G. Roberts1, Yongjin Li 2, Jinghui Zhang2, Richard C. Harvey3, Debbie PayneTurner1, Marcus Valentine4, Kelly McCastlain1, John Easton2, IMing Chen3, Michael Rusch2, Steven M. Kornblau5, Marina Konopleva5, Elisabeth Paietta6, Jacob M. Rowe7, ChingHon Pui 8, Julie M. GastierFoster9, Shalini Reshmi 9, Mignon L. Loh10, Cheryl Willman3, James R. Downing1, Stephen P. Hunger11, and Charles G. Mullighan1 +
Author Affiliations
Proceedings: AACR 106th Annual Meeting 2015; April 1822, 2015; Philadelphia, PA
Abstract Introduction: Phlike acute lymphoblastic leukemia (ALL) is characterized by a diverse range of genetic alterations that activate cytokine receptor and kinase signaling. We recently identified (Roberts KG, NEJM 2014) rearrangements of the erythropoietin receptor (EPOR) with immunoglobulin heavy (IGH) or kappa (IGK) chain loci in 154 Phlike ALL. Here, we aimed to investigate their spectrum and recurrence in an extended cohort, as well as their pathogenic role and therapeutic potential in childhood Phlike ALL. Methods: Whole transcriptome sequencing, realtime quantitative PCR (qPCR) and Sanger sequencing were performed to detect and map the EPOR rearrangements in 307 Phlike ALL. Wildtype or EPOR rearranged alleles were expressed in IL3dependent mouse hematopoietic Ba/F3 cells and IL7dependent preB cells harboring alterations of Arf and/or the dominant negative IKZF1 allele IK6. Proliferation and downstream EPOR signaling were examined in absence or presence of erythropoietin (EPO). Leukemic growth was monitored in C57BL/6 mice transplanted with Arf/ preB cells expressing rearranged EPOR. Luciferase marked xenografts were established in NODSCIDIL2R gamma (NSG) null mice. Signaling, EPOdependent proliferation and sensitivity to the JAK inhibitors were assessed ex vivo and in vivo. Results: EPOR rearrangements were identified in 8.3% of Phlike ALL as the result of: i) inversion and cryptic insertion under the promoter region of IGH/IGK; ii) reciprocal translocation; or iii) fusion to 5′ LAIR1. All rearrangements resulted in ectopic overexpression of a Cterminal truncated receptor, confirmed by qPCR, that retained the phosphorylation site required for STAT5 activation, but lacked multiple tyrosine residues required for normal negative regulation. The rearranged alleles were expressed at higher and more prolonged levels than wildtype EPOR in Ba/F3 and Arf/ mouse preB cells, and sustained cell proliferation with increased STAT5 phosphorylation following exogenous EPO stimulation. In vivo, the truncated receptor promoted leukemia development in C57BL/6 mice. Xenografted EPORrearranged leukemic cells exhibited high levels of truncated EPOR, STAT5 phosphorylation and ex vivo sensitivity to JAK2 inhibition using ruxolitinib, fedratinib, momelotinib, or pacritinib alone or in combination with daunrobucin, vincristine or dexamethasone (synergistic effect). The efficacy of Jak2 inhibition and the synergistic effect of combining ruxolitinib and dexamethasone were subsequently demonstrated in vivo. Conclusions: EPOR rearrangements are recurrent in Phlike ALL and result in ectopic expression of truncated EPOR and activation of JAK2STAT5 signaling pathway, sustaining leukemia development in vivo. Xenografted EPORrearranged leukemia cells exhibit ex vivo and in vivo sensitivity to JAK2 inhibitors alone or in combination with chemotherapy. Citation Format: Ilaria Iacobucci, Kathryn G. Roberts, Yongjin Li, Jinghui Zhang, Richard C. Harvey, Debbie PayneTurner, Marcus Valentine, Kelly McCastlain, John Easton, IMing Chen, Michael Rusch, Steven M. Kornblau, Marina Konopleva, Elisabeth Paietta, Jacob M. Rowe, ChingHon Pui, Julie M. GastierFoster, Shalini Reshmi, Mignon L. Loh, Cheryl Willman, James R. Downing, Stephen P. Hunger, Charles G. Mullighan. Rearrangements of the erythropoietin receptor are recurrent in Phlike acute lymphoblastic leukemia and are sensitive to Jak2 inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 1822; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4369. doi:10.1158/1538 7445.AM20154369 ©2015 American Association for Cancer Research.
http://cancerres.aacrjournals.org/content/75/15_Supplement/4369.short
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