Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, y... more Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T-ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCαS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCα potential as a prognostic biomarker, PKCα expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCα expression with the highest discrimination for incidence of relapse was identified. Patients with PKCα down-regulation, compared to patients with PKCα levels...
Lab-on-a-chip systems with molecular motor driven transport of analytes attached to cytoskeletal ... more Lab-on-a-chip systems with molecular motor driven transport of analytes attached to cytoskeletal filament shuttles (actin filaments, microtubules) circumvent challenges with nanoscale liquid transport. However, the filaments have limited cargo-carrying capacity and limitations either in transportation speed (microtubules) or control over motility direction (actin). To overcome these constraints we here report incorporation of covalently attached antibodies into self-propelled actin bundles (nanocarriers) formed by cross-linking antibody conjugated actin filaments via fascin, a natural actin-bundling protein. We demonstrate high maximum antigen binding activity and propulsion by surface adsorbed myosin motors. Analyte transport capacity is tested using both protein antigens and microvesicles, a novel class of diagnostic markers. Increased incubation concentration with protein antigen in the 0.1-100 nM range (1 min) reduces the fraction of motile bundles and their velocity but maximum...
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts f... more T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of paediatric and 25% of adult ALL cases and is considered a paradigm for the multistep nature of cancer initiation and progression. Genetic and epigenetic reprogramming events, which transform T-cell precursors into malignant T-ALL lymphoblasts, have been extensively characterized over the past decade. Despite our comprehensive understanding of the genomic landscape of human T-ALL, leukemia patients are nowadays still treated by high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable acute and long-term side effects, about 15% of paediatric and 40% of adult T-ALL patients still relapse due to acquired therapy resistance and present with very dismal survival perspectives. Unfortunately, the molecular mechanisms by which residual T-ALL tumor cells survive chemotherapy and act as a reservoir for leukemic progression and hematological relapse remain poorly understood. Nevertheless, it is expected that enhanced molecular understanding of T-ALL disease biology will ultimately facilitate a targeted therapy driven approach that can reduce chemotherapy associated toxicities and improve survival of refractory T-ALL patients through personalized salvage therapy. In this review, we summarize recent biological insights in the molecular pathogenesis of T-ALL and speculate how the genetic landscape of T-ALL could trigger the development of novel therapeutic strategies for the treatment of human T-ALL.
In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effe... more In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could b...
Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, y... more Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T-ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCαS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCα potential as a prognostic biomarker, PKCα expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCα expression with the highest discrimination for incidence of relapse was identified. Patients with PKCα down-regulation, compared to patients with PKCα levels...
Lab-on-a-chip systems with molecular motor driven transport of analytes attached to cytoskeletal ... more Lab-on-a-chip systems with molecular motor driven transport of analytes attached to cytoskeletal filament shuttles (actin filaments, microtubules) circumvent challenges with nanoscale liquid transport. However, the filaments have limited cargo-carrying capacity and limitations either in transportation speed (microtubules) or control over motility direction (actin). To overcome these constraints we here report incorporation of covalently attached antibodies into self-propelled actin bundles (nanocarriers) formed by cross-linking antibody conjugated actin filaments via fascin, a natural actin-bundling protein. We demonstrate high maximum antigen binding activity and propulsion by surface adsorbed myosin motors. Analyte transport capacity is tested using both protein antigens and microvesicles, a novel class of diagnostic markers. Increased incubation concentration with protein antigen in the 0.1-100 nM range (1 min) reduces the fraction of motile bundles and their velocity but maximum...
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts f... more T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of paediatric and 25% of adult ALL cases and is considered a paradigm for the multistep nature of cancer initiation and progression. Genetic and epigenetic reprogramming events, which transform T-cell precursors into malignant T-ALL lymphoblasts, have been extensively characterized over the past decade. Despite our comprehensive understanding of the genomic landscape of human T-ALL, leukemia patients are nowadays still treated by high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable acute and long-term side effects, about 15% of paediatric and 40% of adult T-ALL patients still relapse due to acquired therapy resistance and present with very dismal survival perspectives. Unfortunately, the molecular mechanisms by which residual T-ALL tumor cells survive chemotherapy and act as a reservoir for leukemic progression and hematological relapse remain poorly understood. Nevertheless, it is expected that enhanced molecular understanding of T-ALL disease biology will ultimately facilitate a targeted therapy driven approach that can reduce chemotherapy associated toxicities and improve survival of refractory T-ALL patients through personalized salvage therapy. In this review, we summarize recent biological insights in the molecular pathogenesis of T-ALL and speculate how the genetic landscape of T-ALL could trigger the development of novel therapeutic strategies for the treatment of human T-ALL.
In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effe... more In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could b...
Uploads