High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response

Remke, Marc; Pfister, Stefan M.; Kox, Corinne; Toedt, Grischa; Becker, Natália; Benner, Axel; Werft, Wiebke; Breit, Stephen; Liu, Shuangyou; Engel, Felix B.; Wittmann, Andrea; Zimmermann, Martin; Stanulla, Martin; Schrappe, Martin; Ludwig, Wolf Dieter; Bartram, Claus R.; Radlwimmer, Bernhard; Muckenthaler, Martina U.; Lichter, Peter; Kulozik, Andreas E.

doi:10.1182/blood-2008-10-186536

Cited by 103 publications

(96 citation statements)

References 49 publications

(65 reference statements)

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“…Mutations or rearrangements in KRAS, NRAS, NF1, PTEN, PIK3R1, PIK3CA, AKT, ABL, and JAK1 occur in ≈60% of T-ALL (10)(11)(12)(13)(15)(16)(17)(18)(19), and identifying mutations in other signaling proteins may uncover new therapeutic targets. The uniform sensitivity of our diverse panel of cell lines to a PI3K inhibitor is consistent with emerging genetic data implicating deregulated PI3K/PTEN/Akt signaling as playing a pivotal role in T lineage leukemogenesis (15)(16)(17)(18)(19). Together, these studies and the observed synergy between Compound E and PI-103 support initiating preclinical and clinical trials of PI3K pathway inhibitors-both alone and in combination with GSIs-in T-ALL.…”

Section: Discussionmentioning

confidence: 99%

“…The PTEN tumor suppressor, which encodes a lipid phosphatase that negatively regulates the phosphoinosityl 3-kinase (PI3K)/Akt signaling pathway, is mutated in 5-8% of T-ALLs, and reduced expression was observed in an additional 17% of cases (15,16). Recent studies that uncovered PI3K pathway mutations in ≈50% of pediatric T-ALLs underscore the central role of this Ras effector cascade in leukemic growth (17)(18)(19).…”

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confidence: 99%

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Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Dail¹,

Li²,

McDaniel³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras G12D mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes Kras G12D expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to γ-secretase inhibition. In addition, Kras G12D T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras G12D , and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Dail¹,

Li²,

McDaniel³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…[7,[42][43][44] No mutations have been identified in any AKT isoform in childhood cancer; however, chromosomal gains amplifying the AKT1 gene have been described recently in rare cases of childhood AML, T-cell ALL, and gliosarcoma. [45][46][47] Amplification of eIF4E, S6K1, and cyclin D have been reported in adult cancers, including breast and mantle cell lymphomas but not in pediatric tumors. [48][49][50][51] mTOR-specific mutations in human cancer are extremely rare, with only two reported cases in adult carcinomas.…”

Section: Pi3k/akt/mtor Signaling In Cancermentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…26,27 Restoring PTEN levels in these cell lines decreased cell size and induced apoptosis by suppressing the PI3K-AKT pathway. 28 Studies by others [29][30][31][32][33][34] and our group 21,35 revealed aberrations in the PTEN-PI3K-AKT pathway in approximately 23% of primary samples obtained from pediatric T-ALL patients. With respect to T-ALL subtypes, we have shown that PTEN aberrations are strongly associated with TAL-or LMO-rearranged leukemia in children 21 and the same was observed in adult T-ALL cohorts.…”

Section: Pten Aberrations In T-cell Acute Lymphoblastic Leukemiamentioning

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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High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response

Abstract: Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents

Cited by 103 publications

References 49 publications

Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

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

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High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response

Abstract: Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents

Cited by 103 publications

References 49 publications

Mutant Ikzf1, Kras G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Mutant Ikzf1, Kras G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

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

Contact Info

Product

Resources

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Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents

Mutant Ikzf1, Kras ^G12D , and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents