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postgraduate thesis: Function of SOX7 in normal hematopoiesis and in acute lymphoblastic leukemia

TitleFunction of SOX7 in normal hematopoiesis and in acute lymphoblastic leukemia
Authors
Advisors
Advisor(s):Leung, AYH
Issue Date2012
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Wan, H. [万海霞]. (2012). Function of SOX7 in normal hematopoiesis and in acute lymphoblastic leukemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5137970
AbstractThe SOX (Sry-related HMG box) genes belong to a family of transcription factors containing a High-Mobility-Group box domain. In an initial screen, SOX7 was uniquely down-regulated in myeloid malignancies compared with most cases of precursor B-cell acute lymphoblastic leukemia (ALL) and normal bone marrow cell, leading us to examine the expression and function of SOX7 during normal hematopoietic differentiation and in acute lymphoblastic leukemia. By studying human umbilical cord blood (UCB), SOX7 expression in different hematopoietic lineages was evaluated by RT-PCR. SOX7 was preferentially expressed in CD34+CD38- compared with CD34+CD38+ population and in CD34-CD19+ compared with CD34-CD33+ cells. SOX7 expression was down-regulated in colonies in CFU assay and in engrafting myeloid cells in NOD/SCID mouse transplantation. Transfecting SOX7 siRNA into CD34+ cells reduced cell growth and the CD34+CD33+ population in 3-day culture; induced cell-cycle arrest at G1 phase; reduced clonogenic activities but had no effect on apoptosis. Overall engraftment into NOD/SCID mice were not affected but the engrafting myeloid populations were reduced. In acute lymphoblastic leukemia, SOX7 was robustly expressed, compared with that in normal UCB and acute myeloid leukemia (AML). In 5 ALL patients in whom the coding sequence of SOX7 was examined, 3 of them showed mutations (amino acid change) in the SOX C-terminal transactivation domain. No mutation was observed in the β-catenin binding site. Knockdown of SOX7 with specific siRNA significantly increased appoptosis and decreased cell proliferation. SOX7 knockdown by shRNA in a precursor B-cell ALL cell line Nalm20 significantly reduced its engraftment into NOD/SCID mice. In summary, SOX7 is preferentially expressed in early hematopoietic stem and progenitor cells and is important for the maintenance of myeloid progenitor. It is also expressed in the primitive population of ALL and is important for leukemia initiation in ALL. The present study has generated important information about the regulation of normal hematopoiesis and acute lymphoblastic leukemia
DegreeDoctor of Philosophy
SubjectLymphoblastic leukemia - Genetic aspects
Hematopoiesis
Dept/ProgramMedicine
Persistent Identifierhttp://hdl.handle.net/10722/194606

 

DC FieldValueLanguage
dc.contributor.advisorLeung, AYH-
dc.contributor.authorWan, Haixia-
dc.contributor.author万海霞-
dc.date.accessioned2014-02-14T23:10:56Z-
dc.date.available2014-02-14T23:10:56Z-
dc.date.issued2012-
dc.identifier.citationWan, H. [万海霞]. (2012). Function of SOX7 in normal hematopoiesis and in acute lymphoblastic leukemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5137970-
dc.identifier.urihttp://hdl.handle.net/10722/194606-
dc.description.abstractThe SOX (Sry-related HMG box) genes belong to a family of transcription factors containing a High-Mobility-Group box domain. In an initial screen, SOX7 was uniquely down-regulated in myeloid malignancies compared with most cases of precursor B-cell acute lymphoblastic leukemia (ALL) and normal bone marrow cell, leading us to examine the expression and function of SOX7 during normal hematopoietic differentiation and in acute lymphoblastic leukemia. By studying human umbilical cord blood (UCB), SOX7 expression in different hematopoietic lineages was evaluated by RT-PCR. SOX7 was preferentially expressed in CD34+CD38- compared with CD34+CD38+ population and in CD34-CD19+ compared with CD34-CD33+ cells. SOX7 expression was down-regulated in colonies in CFU assay and in engrafting myeloid cells in NOD/SCID mouse transplantation. Transfecting SOX7 siRNA into CD34+ cells reduced cell growth and the CD34+CD33+ population in 3-day culture; induced cell-cycle arrest at G1 phase; reduced clonogenic activities but had no effect on apoptosis. Overall engraftment into NOD/SCID mice were not affected but the engrafting myeloid populations were reduced. In acute lymphoblastic leukemia, SOX7 was robustly expressed, compared with that in normal UCB and acute myeloid leukemia (AML). In 5 ALL patients in whom the coding sequence of SOX7 was examined, 3 of them showed mutations (amino acid change) in the SOX C-terminal transactivation domain. No mutation was observed in the β-catenin binding site. Knockdown of SOX7 with specific siRNA significantly increased appoptosis and decreased cell proliferation. SOX7 knockdown by shRNA in a precursor B-cell ALL cell line Nalm20 significantly reduced its engraftment into NOD/SCID mice. In summary, SOX7 is preferentially expressed in early hematopoietic stem and progenitor cells and is important for the maintenance of myeloid progenitor. It is also expressed in the primitive population of ALL and is important for leukemia initiation in ALL. The present study has generated important information about the regulation of normal hematopoiesis and acute lymphoblastic leukemia-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.subject.lcshLymphoblastic leukemia - Genetic aspects-
dc.subject.lcshHematopoiesis-
dc.titleFunction of SOX7 in normal hematopoiesis and in acute lymphoblastic leukemia-
dc.typePG_Thesis-
dc.identifier.hkulb5137970-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5137970-
dc.date.hkucongregation2013-

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