BCR-ABL nuclear entrapment kills human CML cells

Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B

Alessandra Aloisi, Sandra Di Gregorio, Fabio Stagno, Patrizia Guglielmo, Francesca Mannino, Maria Pia Sormani, Paolo Bruzzi, Carlo Gambacorti-Passerini, Giuseppe Saglio, Salvatore Venuta, Rosario Giustolisi, Angelo Messina, Paolo Vigneri

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic signaling pathways. We previously reported that the combination of the ABL kinase inhibitor imatinib mesylate (IM) and the nuclear export inhibitor leptomycin B (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells. To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 patients with CML. The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the 2-drug association was independent of the clinical characteristics of the patients. Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients.

Original languageEnglish
Pages (from-to)1591-1598
Number of pages8
JournalBlood
Volume107
Issue number4
DOIs
Publication statusPublished - Feb 15 2006

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Cells
Cell Nucleus Active Transport
Oncogene Proteins
Polymerase chain reaction
RNA-Directed DNA Polymerase
Reverse Transcriptase Polymerase Chain Reaction
Toxicity
Cytoplasm
Cell Death
Phosphotransferases
leptomycin B
Imatinib Mesylate
Tissue Donors
Association reactions
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

Aloisi, A., Di Gregorio, S., Stagno, F., Guglielmo, P., Mannino, F., Sormani, M. P., ... Vigneri, P. (2006). BCR-ABL nuclear entrapment kills human CML cells: Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. Blood, 107(4), 1591-1598. https://doi.org/10.1182/blood-2005-05-2123

BCR-ABL nuclear entrapment kills human CML cells : Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. / Aloisi, Alessandra; Di Gregorio, Sandra; Stagno, Fabio; Guglielmo, Patrizia; Mannino, Francesca; Sormani, Maria Pia; Bruzzi, Paolo; Gambacorti-Passerini, Carlo; Saglio, Giuseppe; Venuta, Salvatore; Giustolisi, Rosario; Messina, Angelo; Vigneri, Paolo.

In: Blood, Vol. 107, No. 4, 15.02.2006, p. 1591-1598.

Research output: Contribution to journalArticle

Aloisi, A, Di Gregorio, S, Stagno, F, Guglielmo, P, Mannino, F, Sormani, MP, Bruzzi, P, Gambacorti-Passerini, C, Saglio, G, Venuta, S, Giustolisi, R, Messina, A & Vigneri, P 2006, 'BCR-ABL nuclear entrapment kills human CML cells: Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B', Blood, vol. 107, no. 4, pp. 1591-1598. https://doi.org/10.1182/blood-2005-05-2123
Aloisi, Alessandra ; Di Gregorio, Sandra ; Stagno, Fabio ; Guglielmo, Patrizia ; Mannino, Francesca ; Sormani, Maria Pia ; Bruzzi, Paolo ; Gambacorti-Passerini, Carlo ; Saglio, Giuseppe ; Venuta, Salvatore ; Giustolisi, Rosario ; Messina, Angelo ; Vigneri, Paolo. / BCR-ABL nuclear entrapment kills human CML cells : Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. In: Blood. 2006 ; Vol. 107, No. 4. pp. 1591-1598.
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abstract = "The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic signaling pathways. We previously reported that the combination of the ABL kinase inhibitor imatinib mesylate (IM) and the nuclear export inhibitor leptomycin B (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells. To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 patients with CML. The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the 2-drug association was independent of the clinical characteristics of the patients. Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients.",
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