The expression of P-glycoprotein in AML cells with FLT3 internal tandem duplications is associated with reduced apoptosis in response to FLT3 inhibitors

British Journal of Haematology
H M HunterN H Russell

Abstract

P-glycoprotein (pgp), a membrane efflux pump, is recognized to have an anti-apoptotic function. Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) receptor are the most common mutations in acute myeloid leukaemia (AML). Both ITDs and pgp positivity confer an adverse clinical prognosis. FLT3 inhibitors induce variable apoptosis in cell lines transfected with FLT3 ITDs. We studied the effect of herbimycin A, AG1296 and PKC412 on primary AML blasts. All compounds showed significantly higher cell kill after 48-h incubation in samples with an ITD compared with wild type (Herbimicin P < 0.001; AG1296 P = 0.001, PKC412, P = 0.002). Pgp-positive samples were significantly less sensitive to herbimycin and AG1296 than pgp-negative samples, although neither molecule inhibited the efflux function of pgp. The concurrent incubation with the pgp inhibitor PSC833 resulted in an enhanced cell kill in 4/5 ITD pgp-positive samples versus two of nine ITD pgp-negative samples. PKC412 inhibited pgp function and induced cell death in FLT3 ITD/pgp-positive samples. We conclude that AML samples with a FLT3 ITD are more susceptible to these inhibitors than wild-type samples. However, the expression of pgp in cells with FLT3 ITD...Continue Reading

References

Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·M J SmythR W Johnstone
Jun 25, 1998·International Journal of Cancer. Journal International Du Cancer·I UtzJ Hofmann
Sep 29, 1999·Advances in Experimental Medicine and Biology·M PallisN H Russell
Mar 21, 2002·Nature Reviews. Cancer·Michael M GottesmanSusan E Bates
Sep 13, 2003·Leukemia·M Levis, D Small

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Citations

Jan 5, 2006·Annals of Hematology·Michael A Morgan, Christoph W M Reuter
Oct 26, 2007·Cancer Chemotherapy and Pharmacology·Lars MöllgårdSören Lehmann
Oct 20, 2006·International Journal of Hematology·Shinichiro TakahashiMitsuo Kaku
Mar 11, 2011·Briefings in Functional Genomics·Nicole C RoyWarren C McNabb
May 3, 2008·Leukemia & Lymphoma·Keith Pratz, Mark Levis
May 18, 2012·Leukemia & Lymphoma·Barbara Nasiłowska-Adamska, Iwona Solarska
Jul 14, 2010·Oncogene·E WeisbergJ D Griffin
Sep 27, 2018·World Journal of Clinical Oncology·Jianbiao Zhou, Wee-Joo Chng
Jul 6, 2019·Frontiers in Oncology·Ning JiDexin Kong
Dec 6, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christophe MarzacOllivier Legrand
Nov 21, 2020·Journal of Hematology & Oncology·Melat T Gebru, Hong-Gang Wang

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