NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols

Zuurbier, Linda; Homminga, Irene; Calvert, Valerie; Winkel, M.L. te; Buijs-Gladdines, Jessica; Kooi, Clarissa; Smits, Willem K.; Sonneveld, Edwin; Veerman, A. J. P.; Kamps, Willem A.; Horstmann, Martin; Petricoin, Emanuel F.; Pieters, Rob; Meijerink, Jules P.P.

doi:10.1038/leu.2010.204

Cited by 129 publications

(152 citation statements)

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“…Despite major improvements in our understanding of the molecular genetics of T-ALL, [36][37][38][39] the mechanisms that lead to the abnormal proliferation and survival of T-lymphoblasts remain largely unknown. Therefore, treatment of this neoplasm remains a challenge for clinicians.…”

Section: Discussionmentioning

confidence: 99%

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

et al. 2011

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The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be down-modulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(+)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL. Leukemia (2012) 26, 91-100; doi:10.1038/leu.2011.269; published online 4 October 201

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Section: Discussionmentioning

confidence: 99%

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

et al. 2011

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“…35 advances in the molecular typing of leukemia, many new genetic alterations, including mutations and deletions, have been identified. However, their prognostic values have not been widely verified and the results may be controversial [24][25][26][27][28][29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Yang

Hsiao

Chen

et al. 2011

Pediatric Blood & Cancer

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BackgroundThe absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T‐cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T‐cell ALL.ProcedureForty‐five children with T‐cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q‐PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q‐PCR was defined as a fold‐change <0.35.ResultsABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23–53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10–16.42).ConclusionsThe absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T‐cell ALL in Taiwan. Providing patients with T‐cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials. Pediatr Blood Cancer 2012; 58: 846–851. © 2011 Wiley Periodicals, Inc.

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“…21 In diagnostic samples from patients with TALLMO, PTEN is frequently inactivated in the absence of NOTCH-activating mutations. 21,32,36,59 Thus, mutations in PTEN and NOTCH1/FBXW7 are frequently independent genetic events and only co-occur in a small number of patients' primary samples. In those patients who harbor both PTEN mutations and NOTCH1/FBXW7 mutations, the NOTCH1 mutations are usually weakly activating mutations.…”

Section: Pten Is Not Linked a Priori To Resistance To Gamma-secretasementioning

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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NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols

Cited by 129 publications

References 43 publications

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

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

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