title: MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells.
abstract: Blasts from approximately one-third of patients with acute myeloid leukemia (AML) harbor activating mutations in the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase that confer a poor prognosis. The Mucin 1-C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in AML blasts and stem cells; however, there is no known interaction between MUC1-C and FLT3. The present studies demonstrate that MUC1-C associates with wild-type and mutant FLT3 in AML cells. Targeting MUC1-C with the cell-penetrating peptide inhibitor GO-203 disrupts MUC1-C/FLT3 complexes and downregulates FLT3 activation. GO-203 treatment of AML cells was also associated with inhibition of the FLT3 downstream effectors AKT, extracellular signal-regulated kinase, and STAT5. The results further show that AML cells with FLT3-activating mutations and resistant to the FLT3 inhibitor midostaurin/PKC412 are sensitive to GO-203-induced growth arrest and death. Moreover, GO-203 increases sensitivity of mutant FLT3 AML cells to FLT3 inhibitor treatment. These results indicate that MUC1-C contributes to FLT3 activation in AML cells and that targeting MUC1-C inhibits the FLT3 signaling pathway. Our findings support the development of MUC1-C inhibitors alone and in combination with agents that target FLT3 for the treatment of wild-type and mutant FLT3 AML.
authors.affiliation: Dana-Farber Cancer Institute and.
authors.forename: Suiyang
authors.initials: S
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.forename: Dina
authors.initials: D
authors.lastname: Stroopinsky
authors.forename: Hasan
authors.initials: H
authors.lastname: Rajabi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Kimberly
authors.initials: K
authors.lastname: Stegmaier
authors.forename: David
authors.initials: D
authors.lastname: Avigan
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018396:Mucin-1 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C582521:(arginine)9-cysteinyl-glutaminyl-cysteinyl-arginyl-arginyl-lysyl-asparagine; C060192:MUC1 protein, human; D018396:Mucin-1; D015513:Oncogene Proteins; D010455:Peptides; D051941:fms-Like Tyrosine Kinase 3