No abstract

No abstract

IntroductionFLT3 is a class III tyrosine kinase receptor that is composed of an extracellular domain that binds FLT3 ligand (FL), a single-pass transmembrane domain, a short juxtamembrane domain, and an interrupted kinase domain that contains a typical activation loop. [1][2][3] FLT3 is expressed on hematopoietic stem and progenitor cells where it functions in cell differentiation, proliferation, and survival. After translation, FLT3 undergoes glycosylation in the endoplasmic reticulum to form an immature receptor and progresses to the Golgi complex where final glycosylation produces a mature receptor before it translocates to the surface. Once at the surface, FLT3 binding to FL leads to receptor dimerization, autophosphorylation, and activation. 4 The transient activation of FLT3 by FL activates several downstream pathways, including Ras/MAPK, PI3K/AKT, and JAK/STAT. [4][5][6][7][8][9] Besides FL binding, FLT3 can also be constitutively activated by mutation, either internal tandem duplications (ITD) of the juxtamembrane domain or point mutations of the tyrosine kinase domain (TKD), that produce altered signaling. [10][11][12] The ITD mutations result in in-frame repeats of varying length. Most TKD mutations result in missense mutations of the activation loop, most frequently the D835 residue. The activating mutations of FLT3 are found in approximately 30% of patients with acute myeloid leukemia (AML). 13,14 When cytokine-dependent cell lines are engineered to express FLT3 mutations they are transformed to factor independence in vitro. FLT3/ITD knock-in mice and mice whose bone marrow is retrovirally transduced with mutant FLT3 develop a lethal myeloproliferative disease. [15][16][17][18] When combined with other mutations such as MLL-AF9, AML1/ETO, NUP-98/HOXD13, or NPM known to occur in human AML, FLT3/ITD mutations cooperate to cause acute leukemia in the mice. [19][20][21][22] This evidence indicates a cooperative role for FLT3 in leukemia and has led to the development of drugs that target FLT3 kinase activity. Numerous tyrosine kinase inhibitors (TKIs) have been identified that all inhibit FLT3/ITD phosphorylation and are cytotoxic to FLT3/ITD-dependent cells. [23][24][25] Wild-type FLT3 is often inhibited to a lesser extent by many of the FLT3 TKI. Some FLT3 TKI have very little activity against certain FLT3 kinase domain-activating mutations, particularly D835Y, rendering the cells functionally resistant. [26][27][28] In addition, there are several mutations within or outside the drug-binding cleft that have been selected for in vitro or in vivo that impart varying levels of resistance to TKI. 28-32 Thus, newer TKIs or a different class of drugs that can inhibit FLT3 are merited for management of leukemias that express FLT3 as a significant transformative component of malignancy.Statins have been developed to lower cholesterol and total triglyceride levels in patients who are considered to be at risk for heart attack based in part on serum cholesterol levels and are considered to be very safe drugs. 33 ...