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 language | English |
|---|---|
| Pages (from-to) | 1591-1598 |
| Number of pages | 8 |
| Journal | Blood |
| Volume | 107 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2006 |
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ASJC Scopus subject areas
- Hematology
Cite this
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 journal › Article
}
TY - JOUR
T1 - BCR-ABL nuclear entrapment kills human CML cells
T2 - Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B
AU - Aloisi, Alessandra
AU - Di Gregorio, Sandra
AU - Stagno, Fabio
AU - Guglielmo, Patrizia
AU - Mannino, Francesca
AU - Sormani, Maria Pia
AU - Bruzzi, Paolo
AU - Gambacorti-Passerini, Carlo
AU - Saglio, Giuseppe
AU - Venuta, Salvatore
AU - Giustolisi, Rosario
AU - Messina, Angelo
AU - Vigneri, Paolo
PY - 2006/2/15
Y1 - 2006/2/15
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=32644438345&partnerID=8YFLogxK
U2 - 10.1182/blood-2005-05-2123
DO - 10.1182/blood-2005-05-2123
M3 - Article
VL - 107
SP - 1591
EP - 1598
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -