Can one target T-cell ALL?

Abstract

Progress in our understanding of the central genes, pathways, and mechanisms in the pathobiology of T-cell acute lymphoblastic leukemia (T-ALL) has identified key drivers of the disease, opening new opportunities for therapy. Drugs targeting highly prevalent genetic alterations in NOTCH1 and CDKN2A are being explored, and multiple other targets with readily available therapeutic agents, and immunotherapies are being investigated. The molecular basis of T-ALL is reviewed here and potential targets and therapeutic targets discussed.

The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

“…The most frequent rearrangement is NUP214-ABL1 amplification (9q34 amplification), observed in 6% of patients (85), whilst EML1-ABL and ETV6-ABL1 are less common (35). NUP214-ABL is a secondary, subclonal alteration and has not been linked with poor prognosis (86).…”

“…Other options are NOTCH transcriptional complex inhibitors or antibodies against NOCTH1 (105). Cell cycle dysregulation by CDK4/CDK6 altered pathway is another potential target, and CDK4/CDK6 inhibitors (86) such as palbociclib recently entered clinical trials. The constitutive activation of PI3K/AKT/mTOR signaling pathway may also be targeted: several PI3K inhibitors showed antileukemic effects in T-ALL cell lines, whereas mTOR inhibitors seem to prolong survival in T-ALL cells (34).…”

“…BKM120/Buparlisib showed modest efficacy and was tolerable in advanced acute leukemia (only 1 patient with T-ALL) in a recent clinical trial (98). As regards cytokine signaling, JAK-STAT pathway is activated in T-ALL and about 5% of cases are driven by tyrosine kinase oncogene fusions, particularly the NUP214-ABL1 rearrangement (86). JAK inhibitors, such as Ruxolitinib and Tofacitinib, have been studied in preclinical models with activation of IL7R/JAK/STAT pathway (34,86).…”

“…As regards cytokine signaling, JAK-STAT pathway is activated in T-ALL and about 5% of cases are driven by tyrosine kinase oncogene fusions, particularly the NUP214-ABL1 rearrangement (86). JAK inhibitors, such as Ruxolitinib and Tofacitinib, have been studied in preclinical models with activation of IL7R/JAK/STAT pathway (34,86). In addition, imatinib, dasatinib, and nilotinib are all active against NUP214-ABL1-positive T-cells, with different ability to inhibit this kinase and induce apoptosis in preclinical studies (102).…”

New Drug Repositioning Candidates for T-ALL Identified Via Human/Murine Gene Signature Comparison

“…Also, 70% of T-ALL have lost the P16/ INK4A, P19/ARF tumor suppressors leading to unrestrained stimulation of cyclin-CDK complexes and cell cycle progression on one arm and inactivation of the p53 tumor suppressor response on the other. These dysregulated events are being investigated as targets of future treatments (5,13). In parallel, ex vivo drug profiling to evaluate the chemosensitivity of relapse samples could be another powerful approach to propose new therapeutic options for some T-ALL subgroups or individual patients (14).…”