MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia

Canté-Barrett, Kirsten; Spijkers-Hagelstein, J A P; Buijs-Gladdines, Jessica; Uitdehaag, Joost C.M.; Smits, Willem K.; Zwet, Jordy Van Der; Buijsman, Rogier C.; Zaman, Guido J.R.; Pieters, Rob; Meijerink, Jules P.P.

doi:10.1038/leu.2016.83

Cited by 82 publications

(90 citation statements)

References 66 publications

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“…All mutant signaling molecules expressed from doxycycline-inducible expression constructs—including IL7R RFCPH , JAK1 R724H , JAK1 T901A , JAK3 M511I , JAK3 R657Q , NRAS G12D , and AKT E17K —were able to trigger IL3-independent growth in Ba/F3 cells, in contrast to their wild-type isoforms, confirming that these mutations can transform cells [41]. In SUPT1 and P12 Ichikawa T-ALL backgrounds, expression of the cysteine mutant IL7R RFCPH conferred steroid resistance, while the wild-type IL7R and the non-cysteine IL7R GPSL mutant receptors did not (S5 Fig).…”

Section: Resultsmentioning

confidence: 98%

“…Surprisingly, JAK3 mutations did not confer resistance (Fig 4E and 4F), while expression of wild-type NRAS, NRAS G12D , and wild-type AKT strongly conferred resistance to steroids (Figs 4G and S5). Although AKT E17K behaves as an activating mutant [42] that supports IL3-independent growth in Ba/F3 cells [41], it did not confer steroid resistance in SUPT1 or P12 Ichikawa cells. We therefore denoted bulk lines that expressed IL7R RFCPH , JAK1 R724H , JAK1 T901A , NRAS G12D , or wild-type NRAS or AKT as the “steroid-resistant panel,” whereas lines that expressed wild-type IL7R, JAK1, or JAK3 or mutant JAK3 M511I , JAK3 R657Q , or AKT E17K as the “steroid-sensitive panel.” The expression of particular (mutant) IL7R signaling molecules specifically affected steroid response since all lines displayed comparable sensitivities to vincristine and L -asparaginase treatments (Figs 4H, 4I and S5).…”

Section: Resultsmentioning

confidence: 99%

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IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

et al. 2016

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BackgroundPediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment.Methods and FindingsWe performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome.To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild-type and mutant IL7R signaling molecules in two steroid-sensitive T-ALL cell lines (SUPT1 and P12 Ichikawa cells) using inducible lentiviral expression constructs. We found that expressing mutant IL7R, JAK1, or NRAS, or wild-type NRAS or AKT, specifically induced steroid resistance without affecting sensitivity to vincristine or L-asparaginase. In contrast, wild-type IL7R, JAK1, and JAK3, as well as mutant JAK3 and mutant AKT, had no effect. We then performed a functional study to examine the mechanisms underlying steroid resistance and found that, rather than changing the steroid receptor’s ability to activate downstream targets, steroid resistance was associated with strong activation of MEK-ERK and AKT, downstream components of the IL7R signaling pathway, thereby inducing a robust antiapoptotic response by upregulating MCL1 and BCLXL expression. Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid-induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM. Importantly, treating our...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

et al. 2016

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“…The viability of pediatric T-ALL cell samples slowly decreases over a period of three days in tissue culture and treatment with several drugs increases cell death [46]. For example, daunorubicin, an established drug for leukemia, killed all viable cells in the patient samples within a period of three days with IC 50 < 100 nM (Table 3).…”

Section: Resultsmentioning

confidence: 99%

Stable aneuploid tumors cells are more sensitive to TTK inhibition than chromosomally unstable cell lines

et al. 2017

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Inhibition of the spindle assembly checkpoint kinase TTK causes chromosome mis-segregation and tumor cell death. However, high levels of TTK correlate with chromosomal instability (CIN), which can lead to aneuploidy. We show that treatment of tumor cells with the selective small molecule TTK inhibitor NTRC 0066-0 overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells NTRC 0066-0 induced acute CIN, whereas in cells with high levels of pre-existing CIN there was only a small additional fraction of cells mis-segregating their chromosomes. In proliferation assays stable aneuploid cells were more sensitive than cell lines with pre-existing CIN. Tetraploids are thought to be an intermediate between diploid and unstable aneuploid cells. TTK inhibitors had the same potency on post-tetraploid and parental diploid cells, which is remarkable because the post-tetraploids are more resistant to mitotic drugs. Finally, we confirm that the reference compound reversine is a TTK inhibitor and like NTRC 0066-0, inhibits the proliferation of patient-derived colorectal cancer organoids. In contrast, treatment with TTK inhibitor did not reduce the viability of non-proliferating T cell acute lymphoblastic leukemia cells samples. Consequently, TTK inhibitor therapy is expected to spare non-dividing cells, and may be used to target stable aneuploid tumors.

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“…For example, mutations in IL7 receptor (IL7R) and the downstream molecules JAK or RAS are prevalent among TLX and ETP-ALL patients. [8][9][10] Although new therapeutic strategies that target oncogenic transcription factor complexes are emerging, 11 several compounds that selectively inhibit altered signaling pathways are currently available. Thus, inhibiting signaling proteins such as NOTCH, IL7R, RAS and/or AKT may provide a promising new therapeutic approach for T-ALL.…”

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confidence: 99%

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of developing T cells in the thymus. T-ALL is characterized by chromosomal rearrangements. These rearrangements can lead to the aberrant activation of oncogenic transcription factors by placing their genes under the control of promoters and/or enhancers of Tcell receptor genes, the BCL11B gene, or other genes; occasionally, these rearrangements can give rise to oncogenic fusion proteins. The activated oncogenic transcription factors include TAL1 and LMO2 (and related family members), TLX1, TLX3, NKX2-1, HOXA, and MEF2C; in addition, certain oncogenic fusion proteins can directly activate the HOXA or MEF2C genes.1,2 Oncogenic proteins facilitate the developmental arrest of pre-leukemic immature T cells. We previously proposed that these chromosomal rearrangements should be classified as type A aberrations, as they are generally considered to be the driving oncogenic event associated with unique expression profiles.2 Based upon their gene expression signatures, T-ALL can be classified into the following four major subtypes: ETP-ALL, TLX, proliferative, and TALLMO. [3][4][5] Maturation arrest induces a pre-leukemic condition in which additional mutations can give rise to T-ALL.1,2 These secondary mutations are not necessarily clonal events and are often selected during disease progression or post-treatment T he tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycoly sis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.

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MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia

Cited by 82 publications

References 66 publications

IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study

Stable aneuploid tumors cells are more sensitive to TTK inhibition than chromosomally unstable cell lines

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

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