From the outside, from within: Biological and therapeutic relevance of signal transduction in T-cell acute lymphoblastic leukemia

Oliveira, Mariana L.; Akkapeddi, Padma; Alcobia, Isabel; Almeida, Afonso R. M.; Cardoso, Bruno; Fragoso, Rita; Serafim, Teresa L.; Barata, João T.

doi:10.1016/j.cellsig.2017.06.011

Cited by 25 publications

(30 citation statements)

References 291 publications

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“…Recent discoveries regarding the genetic basis of T-ALL have provided new insight in the development of this malignancy and we now have a good overview of the various pathways that are altered in T-ALL. 3 , 29 However, many of the in vitro model systems used to study developmental and oncogenic T-cell signaling pathways ex vivo can be limiting due to either not being physiological or require the use of feeder-cell lines. Here we analyzed the pro-T-cell culture system as a new cellular model and show using a systems biology approach that pro-T cells recapitulate thymic T cell at the DN2–DN3 stage.…”

Section: Discussionmentioning

confidence: 99%

Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system

et al. 2017

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T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited robust T-cell model systems. Here we utilize a new ex vivo pro-T-cell model to study oncogenic cooperation. Using a systems biological approach we first dissect the pro-T-cell signaling network driven by interleukin-7, stem cell factor and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T-cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the tricarboxylic acid cycle. This ex vivo pro-T-cell system thereby provides a powerful new model system to investigate how normal T-cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T-ALL.

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Section: Discussionmentioning

confidence: 99%

Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system

et al. 2017

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“…Frequently, the aberrant activation of these signaling pathways crucial to normal T-cell development and implicated in the pathogenesis of T-ALL, is due to genetic alterations of components of these pathways. However, it is becoming clear that bidirectional cross-talk between the microenvironment and leukemic cells exists and that microenvironmental cues ultimately contribute to tumor cell proliferation and survival [ 47 ]. Amongst the intracellular signaling pathways activated by genetic alterations (excluding oncogenic NOTCH1 signaling and CDKN2A / CDKN2B alterations) we find: (1) increased kinase signaling through: (i) the PI3K/AKT/mechanistic target of rapamycin (mTOR) [PI3K/AKT/mTOR] pathway, most commonly altered by PTEN deletion/mutations, PTPN2 deletion, PIK3R1 or v-akt murine thymoma viral oncogene homolog 1 ( AKT1 ) mutations; (ii) the IL-7R/JAK/STAT pathway, via activating mutations in the interleukin 7 receptor α-chain gene ( IL-7Rα ), Janus kinase 1 ( JAK1 ), JAK3 or signal transducer and activator of transcription 5B ( STAT5B ); (iii) the RAS/mitogen-activated protein kinase (RAS/MAPK) signaling through Kirsten rat sarcoma viral oncogene homolog ( KRAS ) and neurofibromin 1 ( NF1 ) mutations; and (iv) via chimeric ABL1 fusion genes such as nucleoporin 214kDa-Abelson murine leukemia viral oncogene homolog 1 (NUP214)-ABL1 and ETS Variant 6-Abelson murine leukemia viral oncogene homolog 1 (ETV6)-ABL1; (2) altered epigenetic regulation through mutations affecting (i) PHF6 ; (ii) PRC2 components EZH2 , SUZ12 and EED ; (iii) KMT2A [also called ubiquitously transcribed tetratricopeptide repeat, X chromosome ( UTX )] reviewed in [ 48 ]; (3) altered ribosomal function through mutations affecting Ribosomal protein L5 ( RPL5 ), Ribosomal protein L10 ( RPL10 ), Ribosomal protein L22 ( RPL22 ) or CCR4-NOT transcription complex subunit 3 ( CNOT3 ) [ 43 ]; and (4) altered expression of oncogenic miRNAs (onco-miRs) such as miR-19b, miR-20a, miR-26a, miR-92, and miR-223 or long noncoding RNAs (lncRNAs) such as leukemia-induced non coding activator RNA 1 (LUNAR1) [ 45 ].…”

Section: Signaling Pathways Involved In the Development Of T-allmentioning

confidence: 99%

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

Bongiovanni

Saccomani

Piovan

2017

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy.

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“…Our increased knowledge of genetic alterations has significantly contributed to identify oncogenetic drivers and signaling cascades regulating T-ALL pathophysiology. This has opened the possibility of targeting pathways that are critical to prevent and/or treat relapse [ 8 ]. The mechanistic target of rapamycin (mTOR) is a key effector of signaling networks that are aberrantly regulated in T-ALL and negatively affect patient outcome [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

Evangelisti

Chiarini

McCubrey

et al. 2018

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.

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From the outside, from within: Biological and therapeutic relevance of signal transduction in T-cell acute lymphoblastic leukemia

Cited by 25 publications

References 291 publications

Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system

Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

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