Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia

<i<FMS-like tyrosine kinase 3</i< (<i<FLT3</i<)-internal tandem duplication (<i<FLT3</i<-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with <i<...
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Gespeichert in:

Autor*in:	Shuangshuang Wu [verfasserIn] Holly Edwards [verfasserIn] Deying Wang [verfasserIn] Shuang Liu [verfasserIn] Xinan Qiao [verfasserIn] Jenna Carter [verfasserIn] Yue Wang [verfasserIn] Jeffrey W. Taub [verfasserIn] Guan Wang [verfasserIn] Yubin Ge [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	acute myeloid leukemia Mcl-1 AZD5991 FLT3 FLT3-ITD MRX-2843

Übergeordnetes Werk:	In: Cells - MDPI AG, 2012, 11(2022), 17, p 2752
Übergeordnetes Werk:	volume:11 ; year:2022 ; number:17, p 2752

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cells11172752

Katalog-ID:	DOAJ033540586

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allfields	10.3390/cells11172752 doi (DE-627)DOAJ033540586 (DE-599)DOAJ367c54ab8c64482a8189519778232544 DE-627 ger DE-627 rakwb eng QH573-671 Shuangshuang Wu verfasserin aut Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <i<FMS-like tyrosine kinase 3</i< (<i<FLT3</i<)-internal tandem duplication (<i<FLT3</i<-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with <i<FLT3</i<-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate <i<c-Myc</i< transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome <i<c</i< release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against <i<FLT3</i<-mutated AML in vitro, warranting further development. acute myeloid leukemia Mcl-1 AZD5991 FLT3 FLT3-ITD MRX-2843 Cytology Holly Edwards verfasserin aut Deying Wang verfasserin aut Shuang Liu verfasserin aut Xinan Qiao verfasserin aut Jenna Carter verfasserin aut Yue Wang verfasserin aut Jeffrey W. Taub verfasserin aut Guan Wang verfasserin aut Yubin Ge verfasserin aut In Cells MDPI AG, 2012 11(2022), 17, p 2752 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:11 year:2022 number:17, p 2752 https://doi.org/10.3390/cells11172752 kostenfrei https://doaj.org/article/367c54ab8c64482a8189519778232544 kostenfrei https://www.mdpi.com/2073-4409/11/17/2752 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 17, p 2752
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author	Shuangshuang Wu
spellingShingle	Shuangshuang Wu misc QH573-671 misc acute myeloid leukemia misc Mcl-1 misc AZD5991 misc FLT3 misc FLT3-ITD misc MRX-2843 misc Cytology Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia
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topic_title	QH573-671 Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia acute myeloid leukemia Mcl-1 AZD5991 FLT3 FLT3-ITD MRX-2843
topic	misc QH573-671 misc acute myeloid leukemia misc Mcl-1 misc AZD5991 misc FLT3 misc FLT3-ITD misc MRX-2843 misc Cytology
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title	Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia
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title_full	Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia
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title_sort	inhibition of mcl-1 synergistically enhances the antileukemic activity of gilteritinib and mrx-2843 in preclinical models of <i<flt3</i<-mutated acute myeloid leukemia
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title_auth	Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia
abstract	<i<FMS-like tyrosine kinase 3</i< (<i<FLT3</i<)-internal tandem duplication (<i<FLT3</i<-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with <i<FLT3</i<-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate <i<c-Myc</i< transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome <i<c</i< release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against <i<FLT3</i<-mutated AML in vitro, warranting further development.
abstractGer	<i<FMS-like tyrosine kinase 3</i< (<i<FLT3</i<)-internal tandem duplication (<i<FLT3</i<-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with <i<FLT3</i<-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate <i<c-Myc</i< transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome <i<c</i< release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against <i<FLT3</i<-mutated AML in vitro, warranting further development.
abstract_unstemmed	<i<FMS-like tyrosine kinase 3</i< (<i<FLT3</i<)-internal tandem duplication (<i<FLT3</i<-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with <i<FLT3</i<-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate <i<c-Myc</i< transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome <i<c</i< release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against <i<FLT3</i<-mutated AML in vitro, warranting further development.
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title_short	Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia
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Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of <i<FLT3</i<-Mutated Acute Myeloid Leukemia

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