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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
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Published on: July 15, 2015

M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib-mediated apoptosis

Roberta Riccioni1, Mara Senese, Daniela Diverio

  • 1Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

British Journal of Haematology
|September 28, 2007
PubMed

Insights

Bortezomib effectively induces apoptosis in acute myeloid leukaemia (AML) cells, particularly those with M4/M5 subtypes and FLT3 mutations. This study supports Bortezomib as an anti-leukaemic drug and offers methods to predict patient sensitivity.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukaemia (AML) is a heterogeneous haematological malignancy.
  • Identifying effective therapeutic agents and predictive biomarkers for AML is crucial.

Purpose of the Study:

  • To investigate the sensitivity of primary AML blasts to Bortezomib.
  • To explore factors influencing Bortezomib efficacy and potential combination therapies.

Main Methods:

  • Culturing primary AML blasts from 30 patients.
  • Assessing Bortezomib-induced apoptosis, alone and in combination with TNF-related apoptosis-inducing ligand.
  • Immunophenotypic analysis (M4/M5 subtypes) and FLT3 mutation status determination.
  • Biochemical assays measuring caspase activation and c-FLIP levels.
  • Evaluating Bortezomib effects on leukaemic stem cells with high aldehyde dehydrogenase activity.

Main Results:

  • Bortezomib induced apoptosis in 18/30 AML cases, with moderate sensitivity in the remainder.
  • Tumour necrosis factor-related apoptosis-inducing ligand potentiated Bortezomib's cytotoxic effects.
  • Sensitive AMLs often exhibited M4/M5 subtypes and myelomonocytic features; all FLT3-mutated AMLs were sensitive.
  • Bortezomib activated caspase-8/3 and decreased c-FLIP; high c-FLIP correlated with low sensitivity.
  • Bortezomib demonstrated in vitro killing of leukaemic stem cells.

Conclusions:

  • Bortezomib exhibits significant anti-leukaemic activity against primary AML blasts.
  • AML immunophenotype (M4/M5) and FLT3 mutation status are potential predictors of Bortezomib sensitivity.
  • Cellular FLICE-inhibitory protein (c-FLIP) levels may serve as a biomarker for Bortezomib response.
  • Bortezomib shows promise for targeting leukaemic stem cells in AML.

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