Abstract
T cell acute lymphoblastic leukemia (T-ALL) is a rare hematological malignancy accounting for about only 15% of the pediatric ALL cases. It originates when genetic lesions accumulate in the DNA of immature T cell precursors. Intensive chemotherapy-based regimens have raised the overall survival of T-ALL patients above 80%. Nevertheless, in
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the last two decades, no improvement in the 5- and 10-year overall survival (OS) could be achieved for T-ALL. Despite the good OS, one out of five pediatric T-ALL patients will ultimately die due to the insurgence of a relapse which is often accompanied by a treatment-refractory disease. Furthermore, T-ALL patients and survivors suffer from severe toxicities caused by the intensive treatment, indicating that further intensification of chemotherapy for high-risk and relapsed patients is not feasible. Thus, tailored therapeutical options are of utmost importance to improve survival and limit treatment-induced severe side effects.
Unlocking the capability to evade from terminal differentiation and the ability to escape a differentiation commitment have been recently recognized as additional hallmarks of cancer. Leukemic cells, thanks to the aberrant expression of developmental transcription factors, maintain a progenitor-like state that assures a differentiation arrest and favors an aberrant proliferation. In fact, extensive transcriptome and genome sequencing studies uncovered that the disease drivers of T-ALL are developmental transcription factors which are ectopically expressed due to genomic rearrangements.
Four main T-ALL subtypes have been identified based on gene expression profiles and presence of recurrent genomic aberrations, namely the Early T-cell Precursor – ALL (ETP-ALL), TLX, TLX1/NKX2.1 (also denoted as proliferative), and TAL/LMO.
While direct targeting of aberrant transcription factors is trivial, identification of secondary mutations that act in concert with genetic drivers can provide important opportunities for genomic-driven precision medicine. In particular, protein kinases are the main effectors of signal transduction and regulate every aspects of the cellular phenotype. Kinase aberrations are not the main disease drivers, but secondary mutations in receptors, kinase-coding genes, and their regulators can support leukemogenesis and favor blasts proliferation and survival.
Gene fusions involving kinase-coding genes are rare in T-ALL and often detected only in minor leukemic subclones, therefore limiting the possibilities for a genomic-driven precision medicine approach.
Active signaling pathways and aberrant kinase activities can provide useful information for drug prioritization and the design of effective combination treatments in the context of personalized medicine, in particular when no actionable target is found via a genomic-driven approach.
Mass spectrometry-based phosphoproteomics allows the simultaneous investigation of multiple proteins and signaling routes without the need for any a priori target selection.
No targeted therapy has been approved for the treatment of T-ALL patients yet, and the lack of accurate predictive biomarkers hampers the correct assignment of patients to tailored treatments. Therefore, we aimed to go beyond the genomics of T-ALL to search for non-genomic dependencies that could be exploited as leukemic vulnerabilities. In particular, we performed an unbiased analysis of the proteome and phosphoproteome of T-ALL to uncover relevant signaling pathways and active kinases and leveraged such hyper-active proteins as putative targets for therapy.
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