NDLI: Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia

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Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia

Content Provider	Scilit
Author	Williams, Allen B. Li, Li Nguyen, Bao Brown, Patrick Levis, Mark Small, Donald
Copyright Year	2012
Description	FLT3 is frequently mutated in acute myeloid leukemia (AML), but resistance has limited the benefit of tyrosine kinase inhibitors (TKI). We demonstrate that statins can impair FLT3 glycosylation, thus leading to loss of surface expression and induction of cell death, as well as mitigation of TKI resistance. Immunofluorescence microscopy confirms a reduction in surface localization and an increase in intracellular FLT3/internal tandem duplication (ITD) accumulation. This aberrant localization was associated with increased STAT5 activation but inhibition of both MAPK and AKT phosphorylation. Growth inhibition studies indicate that FLT3/ITD-expressing cells were killed with an IC50 within a range of 0.2-2μM fluvastatin. Several mechanisms of resistance could be circumvented by fluvastatin treatment. An increase in the IC50 for inhibition of phosphorylated FLT3/ITD by lestaurtinib caused by exogenous FLT3 ligand, resistance to sorafenib caused by the D835Y or FLT3/ITD N676K mutations, and activation of the IL-3 compensatory pathway were all negated by fluvastatin treatment. Finally, fluvastatin treatment in vivo reduced engraftment of BaF3 FLT3/ITD cells in Balb/c mice. These results demonstrate that statins, a class of drugs already approved by the US Food and Drug Administration, might be repurposed for the management of FLT3 mutant acute myeloid leukemia cases either alone or in conjunction with FLT3 TKI.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471516/pdf
Ending Page	3079
Page Count	11
Starting Page	3069
DOI	10.1182/blood-2012-01-403493
Journal	Blood
Issue Number	15
Volume Number	120
Language	English
Publisher	American Society of Hematology
Publisher Date	2012-10-11
Access Restriction	Open
Subject Keyword	Research and Experimental Medicine Cell Death Treatment Survival Tki Fluvastatin Phosphorylated Flt3/itd Demonstrate That Statins Journal: Blood (Vol- 125, Issue- 15)
Content Type	Text
Resource Type	Article

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