• Acute Progression of BCR-FGFR1 Induced Murine B-Lympho/Myeloproliferative Disorder Suggests Involvement of Lineages at the Pro-B Cell Stage

      Ren, MingQiang; Tidwell, Josephine A.; Sharma, Suash; Cowell, John K.; GHSU Cancer Center; Department of Pathology (2012-06-6)
      Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19+ IgMâ CD43+ immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19+ IgMâ CD43+ were also either B220+ or B220â , suggesting a block in differentiation at the pro-B cell stage. The B220â phenotype was retained in one of the cell lines while the other was B220+. When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.
    • Functional Dissection of HOXD Cluster Genes in Regulation of Neuroblastoma Cell Proliferation and Differentiation

      Zha, Yunhong; Ding, Emily; Yang, Liqun; Mao, Ling; Wang, Xiangwei; McCarthy, Brian A.; Huang, Shuang; Ding, Han-Fei; GHSU Cancer Center; Department of Pathology; et al. (2012-08-7)
      Retinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13) that are positioned sequentially from 3â ² to 5â ², with HOXD1 at the 3â ² end and HOXD13 the 5â ² end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2)-C cells, with the genes located at the 3â ² end being activated generally earlier than those positioned more 5â ² within the cluster. Individual induction of HOXD8, HOXD9, HOXD10 or HOXD12 is sufficient to induce both growth arrest and neuronal differentiation, which is associated with downregulation of cell cycle-promoting genes and upregulation of neuronal differentiation genes. However, induction of other HOXD genes either has no effect (HOXD1) or has partial effects (HOXD3, HOXD4, HOXD11 and HOXD13) on BE(2)-C cell proliferation or differentiation. We further show that knockdown of HOXD8 expression, but not that of HOXD9 expression, significantly inhibits the differentiation-inducing activity of RA. HOXD8 directly activates the transcription of HOXC9, a key effector of RA action in neuroblastoma cells. These findings highlight the distinct functions of HOXD genes in RA induction of neuroblastoma cell differentiation.
    • Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases

      Teng, Yong; Ren, MingQiang; Cheney, Richard; Sharma, Shruti; Cowell, John K.; GHSU Cancer Center; Department of Pathology (2010-09-28)
      Background:: The WASF3 protein is involved in cell movement and invasion, and to investigate its role in prostate cancer progression we studied the phenotypic effects of knockdown in primary tumors and cell lines.
    • NF-kB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors

      McCarthy, Brian A.; Yang, Liqun; Ding, Jane; Ren, MingQiang; King, William; ElSalanty, Mohammed; Zakhary, Ibrahim; Sharawy, Mohamed; Cui, Hongjuan; Ding, Han-Fei; et al. (2012-05-29)
      Background: Abnormal NF-κB2 activation has been implicated in the pathogenesis of multiple myeloma, a cancer of plasma cells. However, a causal role for aberrant NF-κB2 signaling in the development of plasma cell tumors has not been established. Also unclear is the molecular mechanism that drives the tumorigenic process. We investigated these questions by using a transgenic mouse model with lymphocyte-targeted expression of p80HT, a lymphoma-associated NF-κB2 mutant, and human multiple myeloma cell lines.