An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia

Knoechel, Birgit; Roderick, Justine E.; Williamson, Kaylyn E.; Zhu, Jiang; Lohr, Jens G.; Cotton, Matthew J.; Gillespie, Shawn; Fernandez, Daniel E.; Ku, Manching; Wang, Hongfang; Piccioni, Federica; Silver, Serena J.; Jain, Mohit; Pearson, Daniel S.; Kluk, Michael J.; Ott, Christopher J.; Shultz, Leonard D.; Brehm, Michael A.; Greiner, Dale L.; Gutiérrez, Alejandro; Stegmaier, Kimberly; Kung, Andrew L.; Root, David E.; Bradner, James E.; Aster, Jon C.; Kelliher, Michelle A.; Bernstein, B

doi:10.1038/ng.2913

Cited by 343 publications

(294 citation statements)

References 43 publications

(50 reference statements)

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“…Many reports attribute the effects of BET inhibitors to BRD4 based on experiments in which individual BETs are depleted. 32,58,66,67 It is important to consider that because of the functional overlap of BRD2 and BRD3, it is possible that the combined contribution of these molecules has been underestimated. Future dissection of the mechanisms through which BETs act distinctly or compensate for each other will be critical when considering the development of BET inhibitors directed against specific members of this family.…”

Section: Discussionmentioning

confidence: 99%

Functions of BET proteins in erythroid gene expression

Stonestrom

Hsu

Jahn

et al. 2015

Blood

109

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• BETs promote GATA1 chromatin occupancy and subsequently activate transcription; they are generally not required for repression.• BRD2 and BRD4 are essential for full GATA1 activity whereas BRD3 function overlaps with BRD2.Inhibitors of bromodomain and extraterminal motif proteins (BETs) are being evaluated for the treatment of cancer and other diseases, yet much remains to be learned about how BET proteins function during normal physiology. We used genomic and genetic approaches to examine BET function in a hematopoietic maturation system driven by GATA1, an acetylated transcription factor previously shown to interact with BETs. We found that BRD2, BRD3, and BRD4 were variably recruited to GATA1-regulated genes, with BRD3 binding the greatest number of GATA1-occupied sites. Pharmacologic BET inhibition impaired GATA1-mediated transcriptional activation, but not repression, genome-wide. Mechanistically, BETs promoted chromatin occupancy of GATA1 and subsequently supported transcriptional activation. Using a combination of CRISPRCas9-mediated genomic engineering and shRNA approaches, we observed that depletion of either BRD2 or BRD4 alone blunted erythroid gene activation. Surprisingly, depletion of BRD3 only affected erythroid transcription in the context of BRD2 deficiency. Consistent with functional overlap among BET proteins, forced BRD3 expression substantially rescued defects caused by BRD2 deficiency. These results suggest that pharmacologic BET inhibition should be interpreted in the context of distinct steps in transcriptional activation and overlapping functions among BET family members. (Blood. 2015;125(18):2825-2834 IntroductionThe mammalian bromodomain and extraterminal motif proteins (BETs) have drawn widespread interest as pharmacologic targets for the treatment of various diseases, including hematologic malignancies and solid tumors. [1][2][3][4] Within the BET family, BRD2, BRD3, and BRD4 are ubiquitously expressed in mammalian tissues, whereas BRDT is testis-specific. BETs contain 2 tandem bromodomains that mediate association with chromatin by binding to acetylated histones and transcription factors. [5][6][7][8][9] BETs function in regulatory complexes that impact messenger RNA (mRNA) production at multiple steps of the transcription cycle, such as modifying and remodeling chromatin and promoting transcription elongation. [10][11][12][13][14][15][16][17] Both BRD2 and BRD4 are essential for normal development.18-20 A BRD3 knockout mouse has not been reported.Promising results obtained with pharmacologic BET inhibitors in animal models of malignancy have sparked clinical trials and intensified efforts to better understand BET function. 1,2,4,21 Given the widespread expression and essential functions of BETs, it was initially surprising that BET inhibitors like JQ1 elicit cell-and genespecific responses. These inhibitors block the acetyl-lysine-binding pockets specifically of BET family bromodomains triggering their release from acetylated lysine residues on histones and transcription factors....

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Section: Discussionmentioning

confidence: 99%

Functions of BET proteins in erythroid gene expression

Stonestrom

Hsu

Jahn

et al. 2015

Blood

109

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“…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]. Spurred by these and other promising preclinical studies, several early phase clinical trials with BETi are planned or are underway for both hematologic and other cancer types (NCT01987362, NCT02157636, NCT01713582, NCT01587703 [14]).…”

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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“…72 Accordingly, treatment of T-ALL xenografted mice with the bromodomain protein inhibitor JQ1 results in decreased MYC levels and also reverses MYC-induced resistance to GSI. 73,74 Furthermore, in human T-ALL cell lines, GSI-sensitive cells can be converted to being GSI-resistant by the ectopic expression of MYC. 68,75 Under normal conditions, MYC is phosphorylated by the kinase GSK-3β; phosphorylated MYC is then subjected to ubiquitination by FBXW7 and proteasomemediated degradation ( Figure 2C).…”

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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An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia

Cited by 343 publications

References 43 publications

Functions of BET proteins in erythroid gene expression

Functions of BET proteins in erythroid gene expression

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

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