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

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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

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Urokinase-Type Plasminogen Activator
Acute Myeloid Leukemia
Myeloid Cells
Cell Line
Maximum Tolerated Dose
Plasminogen Activators
Mitogen-Activated Protein Kinases
Blood Cells
Bone Marrow
Phosphorylation
Safety
anthrax toxin
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phospho-MEK1/2 and uPAR expression determine sensitivity of AML blasts to a urokinase-activated anthrax lethal toxin (PrAgU2/LF). / Bekdash, Amira; Darwish, Manal; Timsah, Zahra; Kassab, Elias; Ghanem, Hadi; Najjar, Vicky; Ghosn, Marwan; Nasser, Selim; El-Hajj, Hiba; Bazerbachi, Ali; Liu, Shihui; Leppla, Stephen H.; Frankel, Arthur E.; Abi-Habib, Ralph J.

In: Translational Oncology, Vol. 8, No. 5, 2015, p. 347-357.

Research output: Contribution to journalArticle

Bekdash, A, Darwish, M, Timsah, Z, Kassab, E, Ghanem, H, Najjar, V, Ghosn, M, Nasser, S, El-Hajj, H, Bazerbachi, A, Liu, S, Leppla, SH, Frankel, AE & Abi-Habib, RJ 2015, 'Phospho-MEK1/2 and uPAR expression determine sensitivity of AML blasts to a urokinase-activated anthrax lethal toxin (PrAgU2/LF)', Translational Oncology, vol. 8, no. 5, pp. 347-357. https://doi.org/10.1016/j.tranon.2015.07.001
Bekdash, Amira ; Darwish, Manal ; Timsah, Zahra ; Kassab, Elias ; Ghanem, Hadi ; Najjar, Vicky ; Ghosn, Marwan ; Nasser, Selim ; El-Hajj, Hiba ; Bazerbachi, Ali ; Liu, Shihui ; Leppla, Stephen H. ; Frankel, Arthur E. ; Abi-Habib, Ralph J. / Phospho-MEK1/2 and uPAR expression determine sensitivity of AML blasts to a urokinase-activated anthrax lethal toxin (PrAgU2/LF). In: Translational Oncology. 2015 ; Vol. 8, No. 5. pp. 347-357.
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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.",
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AU - Bekdash, Amira

AU - Darwish, Manal

AU - Timsah, Zahra

AU - Kassab, Elias

AU - Ghanem, Hadi

AU - Najjar, Vicky

AU - Ghosn, Marwan

AU - Nasser, Selim

AU - El-Hajj, Hiba

AU - Bazerbachi, Ali

AU - Liu, Shihui

AU - Leppla, Stephen H.

AU - Frankel, Arthur E.

AU - Abi-Habib, Ralph J.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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