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T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies - PubMed

  • ️Wed Jan 01 2020

Review

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Valentina Cordo' et al. Blood Cancer Discov. 2020.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with T-ALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent T-ALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of T-ALL and gives a comprehensive overview of the novel treatments for patients with T-ALL that are currently under clinical investigation or that are emerging from preclinical research.

Significance: T-ALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

©2020 American Association for Cancer Research.

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Figures

Figure 1.
Figure 1.

Targeted therapies to tackle T-ALL vulnerabilities. Oncogenic NOTCH1 signaling can be inhibited via different strategies such as monoclonal antibodies blocking the NOTCH1 receptor itself (brontictuzumab), monoclonal antibodies blocking the ADAM10 metalloprotease that releases extracellular NOTCH1, gamma-secretase inhibitors (GSI) preventing the release of intracellular ICN1, and SERCA inhibitors that block the maturation of NOTCH1 and its localization on the cell surface. Because NOTCH1-mutated T-ALL cases can present higher CXCR4 surface expression, CXCR4 antagonists (plerixafor and BL8040) can be used to tackle NOTCH1-driven T-ALL as well. Immunotherapy approaches for T-ALL include monoclonal antibodies against surface CD38 (daratumumab or isatuximab) as well as CAR T cells directed toward surface CD1, CD5, CD7, and CD38. The increased expression of antiapoptotic BH3 proteins such as BCL2 and BCLXL can be counteracted by the use of BH3 mimetics (venetoclax, navitoclax, and AZD-5991). The oncogenic signaling of ABL1 fusion proteins as well as aberrant activity of Src-family kinases can be inhibited by the tyrosine kinase inhibitors imatinib and dasatinib. The aberrant IL7R signaling cascade can be tackled using multiple targeted agents including JAK inhibitors (ruxolitinib), PIM1 inhibitors (AZD-1208), PI3K inhibitors (buparlisib), AKT inhibitors (MK-2206), mTOR inhibitors (sirolimus, everolimus, or temsirolimus), and MEK inhibitors (selumetinib or trametinib). APR-246 can bind mutant p53 and restore its wild-type, tumor-suppressor function, whereas MDM2 inhibitors (idasanutlin and NVP-HDM201) can prevent wild-type p53 ubiquitination and consequent degradation via the proteasome. Alternatively, tumor-suppressor proteins' degradation can be prevented by proteasome inhibitors (bortezomib). Increased activity of cell-cycle regulators CDK4/6 can be blocked by CDK inhibitors (ribociclib or palbociclib), whereas aberrant transcription induced by BRD4 can be targeted by BET inhibitors (OTX015). Nuclear trafficking of oncogenic mRNA and proteins can be targeted via XPO1 inhibitors (selinexor).

Figure 2.
Figure 2.

Thymocytes' developmental stages and T-ALL subtypes. The ETP-ALL subtype is driven by aberrant MEF2C or HOXA gene expression, presents frequent mutations in the IL7 signaling cascade, and shows higher BCL2 protein expression. Similarly to hematopoietic progenitors, ETP-ALL blasts express stem cell markers such as CD34. The TLX subgroup, driven by either TLX3- or HOXA-activating events, often presents NOTCH1 mutations and, in some cases, expression of the γ/δ T-cell receptor (TCR), in analogy to the precortical γ/δ T-cell progenitors (DN2 stage). The TLX1/NKX2.1 subgroup is driven by either NKX2.1 or TLX1 aberrations. TLX-rearranged cases can present the oncogenic NUP214–ABL1 fusion. The TAL/LMO subgroup, driven by the expression of the oncogenes TAL1 and LMO2, includes the most mature T-ALL cases. As for late cortical (SP) T-cell progenitors, TAL/LMO blasts express mature T-cell surface markers such as CD4, CD8, CD3, and α/β TCR and often present PTEN mutations.

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