Research Article: Overcoming Steroid Resistance in T Cell Acute Lymphoblastic Leukemia

Date Published: December 20, 2016

Publisher: Public Library of Science

Author(s): Steven Goossens, Pieter Van Vlierberghe

Abstract: In a Perspective, Pieter Van Vlierberghe and Steven Goossens discuss Meijerink and colleagues’ findings on steroid resistance in pediatric T cell acute lymphoblastic leukemia.

Partial Text: In this issue of PLOS Medicine, Jules Meijerink and colleagues [4] integrated next-generation sequencing data and genome-wide copy number profiles with ex vivo drug sensitivity and clinical outcome in a large panel of primary T-ALL specimens obtained at diagnosis. Interestingly, the authors found that mutations in the interleukin 7 receptor (IL7R) signaling pathway, including JAK1 and KRAS mutations, were significantly associated with prednisolone resistance and reduced survival in an initial discovery cohort of 69 primary T-ALL samples. Of note, these results are in line with the poor prognostic implications of JAK1 [5] and N/K-RAS [6] mutations that have previously been reported in adult T-ALL. In addition, previous studies have also shown an association between RAS mutations and steroid resistance in the context of precursor B-lineage ALL (B cell acute lymphoblastic leukemia [B-ALL]) [7,8]. Given that various mutations affecting the IL7R signaling cascade have also been reported in precursor B-ALL, it is tempting to speculate that the relation between IL7R signaling and steroid resistance could be a general feature of both T- and B-lineage ALL.

To functionally validate the putative contribution of each of these mutations to steroid resistance in T-ALL, Meijerink and colleagues generated a panel of isogenic tumor lines with inducible expression of IL7R–RAS–MAPK–AKT pathway mutations. Using these elegant in vitro model systems, the authors confirmed that IL7R, JAK1, and NRAS mutations, as well as overexpression of wild-type NRAS or AKT, could drive steroid resistance in human T-ALL cell lines (Fig 2). In contrast, no effect was observed for mutant JAK3 or expression of wild-type JAK1, JAK3, or IL7R.

Meijerink and colleagues’ study has unraveled specific pathways that influence glucocorticoid sensitivity in T-ALL by affecting the balance between pro- and anti-apoptotic factors. Therefore, specific targeting of these signaling cascades could provide a unique opportunity to overcome glucocorticoid resistance in human T-ALL. Indeed, the JAK1 inhibitor ruxolitinib, the MEK inhibitor CI1040, and the AKT inhibitor MK2206 were able to reverse steroid resistance in specific isogenic tumor lines (Fig 3). Interestingly, the authors also showed that the GSK3β inhibitor IX provoked strong steroid resistance in sensitive T-ALL tumor lines, further confirming the pivotal role of this molecule in the regulation of glucocorticoid resistance. Moreover, given the central role for the balance between pro- and anti-apoptotic factors in this process, one could hypothesize that specific targeting of the apoptotic machinery using BCL2 [13] or MCL1 [15] inhibitors could also serve as a useful strategy to alter steroid resistance in the context of malignant T cell transformation.



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