Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

Zheng, Ruyue; Li, Menglin; Wang, Shujuan; Liu, Yanfang

doi:10.1186/s40164-020-00187-x

Cited by 27 publications

(25 citation statements)

References 66 publications

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“…Due to the high prevalence and importance of NOTCH1 activating mutations in T-ALL, targeted therapy on NOTCH1 pathway has been a major interest. This includes γ-secretase inhibitors (GSIs), ADAM inhibitors, SERCA inhibitors, and monoclonal antibodies [180]. Among them, GSIs, that block the activation process of NOTCH receptors by inhibiting proteolytic cleavage, have been tested in preclinical and Phase 1 studies [181,182].…”

Section: Notch1 Activating Mutations In T-allmentioning

confidence: 99%

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci

Kimura

Mullighan

2021

JCM

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Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

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Section: Notch1 Activating Mutations In T-allmentioning

confidence: 99%

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci

Kimura

Mullighan

2021

JCM

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“…While NOTCH1/FBXW7 cannot be used alone as prognostic markers, there is a general agreement in considering the NOTCH signaling as a good candidate for tailored therapy. Preclinical studies have shown a strong therapeutic effect of different NOTCH1 inhibitors, such as γ-Secretase (GS) and ADAM (Disintegrin Metalloproteases) inhibitors, monoclonal antibody, and molecules that block the activity of the NOTCH1 transcription factor complex, in both T-ALL cell lines and primary samples [68]. In addition, therapeutic targeting of the E3 ubiquitin ligase SKP2, whose expression is regulated by NOTCH signaling, has been proven to block T-ALL proliferation in in vitro and in vivo models [69].…”

Section: Actionable Deregulated Pathways and Cellular Processes 61 Notch Pathway Activationmentioning

confidence: 99%

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

Bardelli

Arniani

Pierini

et al. 2021

Genes

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T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.

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“…Additionally, a combination of GSIs and chloroquine has presented a synergistic effect in vitro on the T-ALL cell line and is associated with fewer side effects [40]. Using GSIs as a single agent seems to be insufficient in T-ALL carrying Notch1 mutations, and combined treatments, with reduced gastrointestinal toxicity and enhanced antileukemic effects, may be alternative options [41]. Apart from the limitations and constant improvements in GSI therapy, distinct approaches targeting the NOTCH signaling pathway have been developed, including ADAM10 and CAD204520 SERCA inhibitors.…”

Section: Novel Approach In T-all Treatmentmentioning

confidence: 99%

“…In addition, monoclonal antibodies against the NOTCH1 receptor have shown efficacy in preclinical trials. OMP-52M51, a monoclonal antibody produced by mice immunized by human NOTCH1 protein fragments, showed antitumor effects in a T-ALL cell line in vitro and in vivo in xenograft models [ 41 , 42 ].…”

Section: Novel Approach In T-all Treatmentmentioning

confidence: 99%

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia

Lato

Przysucha

Grosman

et al. 2021

IJMS

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Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10–15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.

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Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

Cited by 27 publications

References 66 publications

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia

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