title: The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia.
abstract: The transcription factor Sox4 plays an indispensable role in the development of early progenitor B cells from hematopoietic stem cells. However, its role in B-cell acute lymphoblastic leukemia, a malignant counterpart of normal progenitor B cells, is not fully understood. Here we show that SOX4 is highly expressed in human acute lymphoblastic leukemia cells. To systematically study the function of Sox4 in acute lymphoblastic leukemia, we established a genetically defined mouse leukemia model by transforming progenitor B cells carrying a floxed Sox4 allele and inducing deletion of the allele by the self-excising Cre recombinase. This model allowed us to work with two groups of leukemic cells that had either one copy or both copies of Sox4 deleted. We found that depletion of Sox4 in transformed cells in vitro reduced cell growth in vitro and the progression of leukemia in vivo. Moreover, depletion of Sox4 in leukemic cells in vivo prolonged the survival of the mice, suggesting that it could be a potential target in acute lymphoblastic leukemia therapy. Our microarray and bioChIP studies revealed that Tcf7l1 was the key gene directly regulated by Sox4. Knockdown of Tcf7l1 reduced cell proliferation, just as did knockout of Sox4, and ectopic expression of Tcf7l1 could reverse the effect of Sox4 knockout on cell proliferation. These data suggest that Sox4 and Tcf7l1 form a functional axis that promotes the progression of BCR-ABL-positive acute lymphoblastic leukemia.
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.
authors.forename: Saradhi
authors.initials: S
authors.lastname: Mallampati
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.
authors.forename: Baohua
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.
authors.forename: Enze
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Pathology, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, TX, and Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Hematopathology, The University of Texas MDACC, Houston, TX, USA.
authors.forename: C Cameron
authors.initials: CC
authors.lastname: Yin
authors.affiliation: School of Health Sciences, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
authors.affiliation: Department of Hematopathology, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.affiliation: Department of Hematopathology, The University of Texas MDACC, Houston, TX, USA.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Pediatrics, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Zweidler-McKay
authors.affiliation: Department of Pathology, Stony Brook University Medical Center, Stony Brook, NY, USA.
authors.forename: Yupo
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Leukemia, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MDACC, Houston, TX, USA.
authors.forename: Ralph B
authors.initials: RB
authors.lastname: Arlinghaus
authors.affiliation: Department of Microbiology and Immunology, The Medical University of South Carolina, Charleston, and Department of Pathology & Laboratory Medicine, The University of Texas Houston Health Science Center, Houston, TX, USA.
authors.forename: Armand
authors.initials: A
authors.lastname: Glassman
authors.affiliation: Department of Laboratory Medicine and the Center for Stem Cell and Developmental Biology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA xsun@mdanderson.org.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D018450:Disease Progression; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058125:Transcription Factor 7-Like 1 Protein / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D055751:SOXC Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D016044:Fusion Proteins, bcr-abl