Phospho-MEK1/2 and uPAR expression determine sensitivity of AML blasts to a urokinase-activated anthrax lethal toxin (PrAgU2/LF)

Amira Bekdash, Manal Darwish, Zahra Timsah, Elias Kassab, Hadi Ghanem, Vicky Najjar, Marwan Ghosn, Selim Nasser, Hiba El-Hajj, Ali Bazerbachi, Shihui Liu, Stephen H. Leppla, Arthur E. Frankel, Ralph J. Abi-Habib

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

In this study, we attempt to target both the urokinase plasminogen activator and the mitogen-activated protein kinase pathway in acute myeloid leukemia (AML) cell lines and primaryAMLblasts using PrAgU2/LF, a urokinase-activated anthrax lethal toxin. PrAgU2/LF was cytotoxic to five out of nine AML cell lines. Cytotoxicity of PrAgU2/LF appeared to be nonapoptotic andwas associated withMAPKactivation and urokinase activity because all the PrAgU2/LF-sensitive cell lines showed both uPAR expression and high levels ofMEK1/2 phosphorylation. Inhibition of uPAR or desensitization of cells to MEK1/2 inhibition blocked toxicity of PrAgU2/LF, indicating requirement for both uPAR expression and MAPK activation for activity. PrAgU2/LF was also cytotoxic to primary blasts from AML patients, with blasts from four out of five patients showing a cytotoxic response to PrAgU2/LF. Cytotoxicity of primary AML blasts was also dependent on uPAR expression and phos-MEK1/2 levels. CD34 + bone marrow blasts and peripheral blood mononuclear cells lacked uPAR expression and were resistant to PrAgU2/LF, demonstrating the lack of toxicity to normal hematological cells and, therefore, the tumor selectivity of this approach. Dose escalation in mice revealed that the maximal tolerated dose of PrAgU2/LF is at least 5.7- fold higher than that of the wild-type anthrax lethal toxin, PrAg/LF, further demonstrating the increased safety of this molecule.Wehaveshown, in thisstudy, thatPrAgU2/LFisanovel, dual-specific molecule for the selective targeting ofAML.

Original languageEnglish (US)
Pages (from-to)347-357
Number of pages11
JournalTranslational Oncology
Volume8
Issue number5
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bekdash, A., Darwish, M., Timsah, Z., Kassab, E., Ghanem, H., Najjar, V., Ghosn, M., Nasser, S., El-Hajj, H., Bazerbachi, A., Liu, S., Leppla, S. H., Frankel, A. E., & Abi-Habib, R. J. (2015). Phospho-MEK1/2 and uPAR expression determine sensitivity of AML blasts to a urokinase-activated anthrax lethal toxin (PrAgU2/LF). Translational Oncology, 8(5), 347-357. https://doi.org/10.1016/j.tranon.2015.07.001