Abstract
ABSTRACTObjective: To summarize the abnormal location of FLT3 caused by different glycosylation status which further leads to the distinguishing signaling pathways and discuss targeting on FLT3 glycosylation by drugs reported in recent literatures.Methods: We review FLT3 glycosylation in endoplasmic reticulum. The abnormal signal of mutant FLT3 with different glycosylation status is discussed. We also address potential FLT3 glycosylation-targeting strategies for the treatment.Results: Inhibition of FLT3 mutant cells by drugs reported in recent literatures involves the influence of glycosylation of FLT3: 2-deoxy-D-glucose, Tunicamycin and Fluvastatin are reported to inhibit N-glycosylation of FLT3; Pim-1 inhibitors are proved to block the inhibition of Pim-1 on FLT3 Oglycosylation; HSP90 inhibitors and Tyrosine Kinase Inhibitors are shown to increase fully glycosylated form of FLT3.Discussion: The FMS-like tyrosine kinase 3 (FLT3) gene expressed only in CD34+ progenitor cells in bone marrow is located on chromosome 13q12 encoding FLT3 protein. FLT3 is initially synthesized as a 110 KD protein, which glycosylated in the endoplasmic reticulum to a 130 KD immature protein rich in mannose, and further processed into a mature 160 KD protein in the Golgi apparatus, which could be transferred to the cell surface. Therapy targeting on FLT3 glycosylation is a promising direction for AML treatment.Conclusions: The abnormal location of FLT3 caused by different glycosylation status leads to the distinguishing signaling pathways. Targeting on FLT3 glycosylation may provide a new perspective for therapeutic strategies.Abbreviations: ABCG2: ATP-binding cassette transporter breast cancer resistance protein; ATF: activating transcription factor; AML: acute myeloid leukemia; CHOP: CCAAT-enhancer-binding protein homologous protein; 2-DG: 2-deoxy-D-glucose; EFS: event free survival; EPO: erythropoietin; EPOR: erythropoietin receptor; ERS: endoplasmic reticulum stress; FLT3: FMS-like tyrosine kinase 3; GPI: glycosylphosphatidylinositol; HSP: heat shock protein; ITD: internal tandem duplication; IRE1a: inositol-requiring enzyme 1 alpha; JNK: c-Jun N-terminal kinase; JMD: juxtamembrane domain; JAK: janus kinase; MAPK/ERK: mitogen activated protein kinase/extracellular signal-regulated protein kinase; OS: overall survival; PI3K/AKT: phosphatidylinositide 3-kinases/protein kinase B; PERK: RNA-activated protein kinase-like endoplasmic reticulum kinase; Pgp: P-glycoprotein; PTX3: human pentraxin-3; STAT: signal transducer and activator of transcriptions; TKD: tyrosine-kinase domain; TKI: tyrosine kinase inhibitor; TM: Tunicamycin; UPR: unfolded protein reaction
Highlights
Acute myeloid leukemia (AML) is a heterogeneous malignant clonal disorder that starts from bone marrow immature myeloid progenitor cells transformed by recurrent genetic alterations to induce leukemic cell proliferation and survival [1]
To summarize the abnormal location of FMS-like tyrosine kinase 3 (FLT3) caused by different glycosylation status which further leads to the distinguishing signaling pathways and discuss targeting on FLT3 glycosylation by drugs reported in recent literatures
The abnormal location of mutant FLT3 is caused by different glycosylation states, and activates the abnormal signaling pathway
Summary
Acute myeloid leukemia (AML) is a heterogeneous malignant clonal disorder that starts from bone marrow immature myeloid progenitor cells transformed by recurrent genetic alterations to induce leukemic cell proliferation and survival [1]. These cells are capable of self-renewing and sustaining malignant populations as well as producing subclones [2]. Activated FLT3 mutation which is one of the most common mutant genes in AML occurs in about 40% of patients with acute myeloid leukemia (AML) with normal cytogenetics [4,5]. The pathway regulates the growth and development of hematopoietic stem/progenitor cells [7]. If FLT3 cannot be glycosylated correctly in Golgi, FLT3 protein will accumulate in the endoplasmic reticulum, causing cells to respond to the unfolded proteins, promoting cell apoptosis [16] or triggering signal pathway different from glycosylation species
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