title: Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The PTEN, PI3K/AKT and Notch pathways are frequently altered in T-ALL. PTEN is a tumor suppressor that inactivates the PI3K pathway. We profiled miRNAs in Pten-deficient mouse T-ALL and identified miR-26b as a potentially dysregulated gene. We validated decreased expression levels of miR-26b in mouse and human T-ALL cells. In addition, expression of exogenous miR-26b reduced proliferation and promoted apoptosis of T-ALL cells in vitro, and hindered progression of T-ALL in vivo. Furthermore, miR-26b inhibited the PI3K/AKT pathway by directly targeting PIK3CD, the gene encoding PI3Kδ, in human T-ALL cell lines. ShRNA for PIK3CD and CAL-101, a PIK3CD inhibitor, reduced the growth and increased apoptosis of T-ALL cells. Finally, we showed that PTEN induced miR-26b expression by regulating the differential expression of Ikaros isoforms that are transcriptional regulators of miR-26b. These results suggest that miR-26b functions as a tumor suppressor in the development of T-ALL. Further characterization of targets and regulators of miR-26b may be promising for the development of novel therapies.
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
authors.forename: T
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Shaoxing University Medical School, Shaoxing City, Zhejiang Province, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Laboratory Medicine, Harbin Medical University Tumor Hospital, Heilongjiang Province, Harbin, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Leukemia, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Leukemia, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: R S
authors.initials: RS
authors.lastname: Goswami
authors.affiliation: Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J Q
authors.initials: JQ
authors.lastname: You
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lin
authors.affiliation: Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Qian
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Calin
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Shaoxing University Medical School, Shaoxing City, Zhejiang Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Miranda
authors.affiliation: Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Division of Pediatric, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.affiliation: Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, the University of British Columbia, Vancouver, BC, Canada.
authors.forename: A P
authors.initials: AP
authors.lastname: Weng
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: You
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051740:Ikaros Transcription Factor; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; C497239:IKZF1 protein, human; C528163:MIRN26 microRNA, human; C486018:PIK3CD protein, human; C494929:PTEN protein, human