c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

Roderick, Justine E.; Tesell, Jessica; Shultz, Leonard D.; Brehm, Michael A.; Greiner, Dale L.; Harris, Marian H.; Silverman, Lewis B.; Sallan, Stephen E.; Gutiérrez, Alejandro; Look, A. Thomas; Qi, Jun; Bradner, James E.; Kelliher, Michelle A.

doi:10.1182/blood-2013-08-522698

Cited by 135 publications

(134 citation statements)

References 50 publications

(66 reference statements)

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“…These BET inhibitors (BETi) effectively displace BET proteins from transcriptionally active regions of chromatin. Interestingly, the growth of many types of leukemia cell lines is inhibited with BETi treatment [6][7][8][9][10][11]. This antiproliferative effect has largely been attributed to the unanticipated dependency of MYC transcription on BRD4.…”

Section: Targeting Bromodomainsmentioning

confidence: 98%

“…Several studies have shown a specific loss of MYC activity in T-ALL leukemia initiating cells with BETi treatment both in in vitro and in vivo experiments. Using mouse models with xenografted T-ALL cells, systemic administration of BETi is relatively well tolerated and leads to a decrease in T-ALL disease burden [10,11]. BET inhibition also seems to effectively target cells resistant to GSI, revealing a potential combination strategy for treatment of this disease [13].…”

Section: Targeting Bromodomainsmentioning

confidence: 99%

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Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

Ott¹

2014

Int. J. Hematol. Oncol.

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Section: Targeting Bromodomainsmentioning

confidence: 98%

Section: Targeting Bromodomainsmentioning

confidence: 99%

Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

Ott¹

2014

Int. J. Hematol. Oncol.

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“…80 Reducing endogenous Myc levels led to increased survival and reduced numbers of leukemia cells with leukemia-initiating cell potential in both models. 79,81 Overall, these positive feedback loops between NOTCH, MYC, and AKT suggest that inhibitors of MYC or PI3K/AKT may help to prevent resistance to NOTCH1-inhibiting therapies, 82 and also eliminate leukemia-initiating cell activity in T-ALL. Co-targeting the PI3K pathway and MYC remarkably enhanced the elimination of leukemia-initiating cells.…”

Section: Rd Mendes Et Almentioning

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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“…In addition to PRC2 mutations in ETP ALL, 13,71 notable examples are mutations of WHSC1 (NSD2) in ETV6-RUNX1 ALL, 80 and mutation of CREBBP (a H3K18, H3K27, and nonhistone acetyl transferase), SETD2 (a H3K36 trimethylase), KDM6A, and MLL2 in relapsed and hypodiploid ALL. 11,15,35,77 Consequently, there is interest in testing the efficacy of drugs that modulate histone modifications in ALL, including inhibitors of bromodomain readers, 81 histone demethylases, 82 and histone deacetylases.…”

Section: Epigenetic Alterations In Allmentioning

confidence: 99%

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

Hunger

Mullighan

2015

Blood

243

198

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Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and remains a leading cause of cancer death in the young. In the last decade, microarray and sequencing analysis of large ALL cohorts has revolutionized our understanding of the genetic basis of this disease. These studies have identified new ALL subtypes, each characterized by constellations of structural and sequence alterations that perturb key cellular pathways, including lymphoid development, cell-cycle regulation, and tumor suppression; cytokine receptor, kinase, and Ras signaling; and chromatin modifications. Several of these pathways, particularly kinase-activating lesions and epigenetic alterations, are logical targets for new precision medicine therapies. Genomic profiling has also identified important interactions between inherited genetic variants that influence the risk of leukemia development and the somatic genetic alterations that are required to establish the leukemic clone. Moreover, sequential sequencing studies at diagnosis, remission, and relapse have provided important insights into the relationship among genetic variants, clonal heterogeneity, and the risk of relapse. Ongoing studies are extending our understanding of coding and noncoding genetic alterations in B-progenitor and T-lineage ALL and using these insights to inform the development of faithful experimental models to test the efficacy of new treatment approaches. (Blood. 2015;125(26):3977-3987)

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c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

Abstract: Key Points c-Myc is required for leukemia-initiating cell maintenance in murine models of T-ALL. c-Myc inhibition prevents the growth of treatment-resistant primary T-ALL patient samples in vitro.

Cited by 135 publications

References 50 publications

Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

Promising New Strategies to Target Gene Regulatory Factors in T-Cell Acute Lymphoblastic Leukemia

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

Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine

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