title: Dysregulated signaling pathways in the development of CNTRL-FGFR1-induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models.
abstract: Myeloid and lymphoid neoplasm associated with FGFR1 is an aggressive disease, and resistant to all the current chemotherapies. To define the molecular etiology of this disease, we have developed murine models of this disease, in syngeneic hosts as well as in nonobese diabetic/severe combined immunodeficiency/interleukin 2Rγ(null) mice engrafted with transformed human CD34+ hematopoietic stem/progenitor cells. Both murine models mimic the human disease with splenohepatomegaly, hypercellular bone marrow, and myeloproliferative neoplasms that progresses to acute myeloid leukemia. Molecular genetic analyses of these model mice, as well as primary human disease, demonstrated that CNTRL-FGFR1, through abnormal activation of several signaling pathways related to development and differentiation of both myeloid and T-lymphoid cells, contribute to overt leukemogenesis. Clonal evolution analysis indicates that myeloid related neoplasms arise from common myeloid precursor cells that retain potential for T-lymphoid differentiation. These data indicate that simultaneously targeting these pathways is essential to successfully treating this almost invariably lethal disease.
authors.affiliation: Georgia Regents University Cancer Center, 1120 15th St, Augusta, GA 30912, USA. mren@gru.edu
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Ren
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.forename: Eiko
authors.initials: E
authors.lastname: Kitamura
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D015723:Gene Library; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009196:Myeloproliferative Disorders / Q000235:genetics*; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: D018952:Antigens, CD34; C474898:CNTRL protein, human; D018797:Cell Cycle Proteins; D007136:Immunoglobulins; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; C084881:flt3 ligand protein; C496348:FGFR1 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051496:Receptor, Fibroblast Growth Factor, Type 1