Janani Kumar

Publications (2)9.29 Total impact

• Article: Alternate TEL-JAK2 fusions associated with T cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia dissected in zebrafish.

  Sara M N Onnebo, Parisa Rasighaemi, Janani Kumar, Clifford Liongue, Alister C Ward
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  ABSTRACT: Background: Chromosomal translocations resulting in alternative fusions of the human TEL (ETV6) and JAK2 genes have been observed in cases of acute lymphoblastic leukemia and chronic myelogenous leukemia, but a full understanding of their role in disease etiology has remained elusive. This study investigated potential differences between these alternate TEL-JAK2 fusions, including their lineage specificity.Design and Methods: Both T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia derived TEL-JAK2 fusion types were generated using the corresponding zebrafish tel and jak2a genes and placed under the control of either the white blood cell-specific spi1 promoter or the ubiquitously-expressed cytomegalovirus promoter. These constructs were injected into zebrafish embryos and their effects on hematopoiesis examined using a range of molecular approaches. In addition, the functional properties of the alternate fusions were investigated in vitro.Results: Injection of the T-cell acute lymphoblastic leukemia derived tel-jak2a significantly perturbed lymphopoiesis with a lesser effect on myelopoiesis in zebrafish embryos. In contrast, injection of the atypical chronic myelogenous leukemia derived tel-jak2a resulted in significant perturbation of the myeloid compartment. These phenotypes were observed regardless of whether expressed in a white blood cell-specific or ubiquitous manner, with no overt cellular proliferation outside of the hematopoietic cells. Functional studies revealed subtle differences between the alternate forms, with the acute lymphoblastic leukemia variant showing higher activity, but reduced downstream Signal Transducer and Activator of Transcription activation and decreased sensitivity to JAK2 inhibition. JAK2 activity was required to mediate the effects of both variants on zebrafish hematopoiesis.Conclusions: This study indicates that the molecular structure of alternate TEL-JAK2 fusions likely contributes to the etiology of disease. The data further suggest that this class of oncogene exerts its effects in a cell lineage-specific manner, which may be due to differences in downstream signalling.
  Haematologica 06/2012; · 6.42 Impact Factor
• Article: Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile.

  Ardian Latifi, Khalid Abubaker, Natalie Castrechini, Alister C Ward, Clifford Liongue, Francoise Dobill, Janani Kumar, Erik W Thompson, Michael A Quinn, Jock K Findlay, Nuzhat Ahmed
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  ABSTRACT: Epithelial mesenchymal transition (EMT) and cancer stem cells (CSC) have been associated with resistance to chemotherapy. Eighty percent of ovarian cancer patients initially respond to platinum-based combination therapy but most return with recurrence and ultimate demise. To better understand such chemoresistance we have assessed the potential role of EMT in tumor cells collected from advanced-stage ovarian cancer patients and the ovarian cancer cell line OVCA 433 in response to cisplatin in vitro. We demonstrate that cisplatin-induced transition from epithelial to mesenchymal morphology in residual cancer cells correlated with reduced E-cadherin, and increased N-cadherin and vimentin expression. The mRNA expression of Snail, Slug, Twist, and MMP-2 were significantly enhanced in response to cisplatin and correlated with increased migration. This coincided with increased cell surface expression of CSC-like markers such as CD44, α2 integrin subunit, CD117, CD133, EpCAM, and the expression of stem cell factors Nanog and Oct-4. EMT and CSC-like changes in response to cisplatin correlated with enhanced activation of extracellular signal-regulated kinase (ERK)1/2. The selective MEK inhibitor U0126 inhibited ERK2 activation and partially suppressed cisplatin-induced EMT and CSC markers. In vivo xenotransplantation of cisplatin-treated OVCA 433 cells in zebrafish embryos demonstrated significantly enhanced migration of cells compared to control untreated cells. U0126 inhibited cisplatin-induced migration of cells in vivo, suggesting that ERK2 signaling is critical to cisplatin-induced EMT and CSC phenotypes, and that targeting ERK2 in the presence of cisplatin may reduce the burden of residual tumor, the ultimate cause of recurrence in ovarian cancer patients.
  Journal of Cellular Biochemistry 05/2011; 112(10):2850-64. · 2.87 Impact Factor