title: Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.
abstract: Acute myeloid leukemia (AML) is sustained by small populations of leukemia stem cells (LSCs) that can resist available treatments and represent important barriers to cure. Although previous studies have shown increased signal transducer and activator of transcription (STAT)3 and STAT5 phosphorylation in AML leukemic blasts, the role of Janus kinase (JAK) signaling in primary AML compared with normal stem cells has not been directly evaluated. We show here that JAK/STAT signaling is increased in LSCs, particularly from high-risk AML. JAK2 inhibition using small molecule inhibitors or interference RNA reduced growth of AML LSCs while sparing normal stem cells both in vitro and in vivo. Increased JAK/STAT activity was associated with increased expression and altered signaling through growth factor receptors in AML LSCs, including receptor tyrosine kinase c-KIT and FMS-related tyrosine kinase 3 (FLT3). Inhibition of c-KIT and FLT3 expression significantly inhibited JAK/STAT signaling in AML LSCs, and JAK inhibitors effectively inhibited FLT3-mutated AML LSCs. Our results indicate that JAK/STAT signaling represents an important signaling mechanism supporting AML LSC growth and survival. These studies support continued evaluation of strategies for JAK/STAT inhibition for therapeutic targeting of AML LSCs.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Cook
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Yinwei
authors.initials: Y
authors.lastname: Ho
authors.forename: Allen
authors.initials: A
authors.lastname: Lin
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Anthony
authors.initials: A
authors.lastname: Stein
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; D018952:Antigens, CD34; D011720:Pyrazoles; D011743:Pyrimidines; D017978:Receptors, Growth Factor; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2; D053612:Janus Kinases