The research object of this proposal is to define the role of the Sonic Hedgehog (SHH) pathway in the biology, pathology, and resistance to chemotherapy of diffuse large B-cell lymphomas (DLBCL), the most common lymphoma worldwide. Although DLBCL is potentially curable wit conventional anthracycline-based therapy, variability in response is often observed and 40-50% patients will relapse and will be not cured with the current available therapies. Our preliminary data provide biological evidence that SHH/GLI signaling pathway plays a role in the pathogenesis of DLBCL. We have also observed high expression of ABCG2, a member of ATP binding cassette family of transporter proteins involved in chemoresistance, in a subset of DLBCL and a positive correlation between expression of ABCG2 and GLI1. Based on these studies, we hypothesize that elevated activity of the SHH signaling pathway promotes DLBCL growth and contributes to chemoresistance in DLBCL. To achieve this aim we will investigate causative factors in the deregulation of SHH/GLI signaling in DLBCL, we will elucidate, in vitro, the biological effect of SHH signaling inhibition using pharmacologic inhibitors as well as silencing the expression of the transducers of the SHH signal, the GLI proteins, and we will uncover the contribution of the SHH signaling in chemoresistance. The effects of inhibiting SHH signaling on lymphoma growth will be also studied in a human DLBCL xenograft model. To investigate the biological role of SHH signaling in DLBCL will provide new insights into the pathogenesis and drug resistance mechanisms of DLBCL, and may contribute to improve the current therapeutic strategies in this lymphoma type.
Diffuse large B-cell lymphoma (DLBC) is the most common aggressive lymphoma worldwide. Understandingthe role of Sonic Hedgehog (SHH) pathway in the biology and resistance to chemotherapy in DLBCL will opennew avenues for targeted therapy in this lymphoma type.
|Agarwal, Nitin K; Kim, Chae H; Kunkalla, Kranthi et al. (2016) Active IKK? promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma. Blood 127:605-15|
|Chapman, J; Gentles, A J; Sujoy, V et al. (2015) Gene expression analysis of plasmablastic lymphoma identifies downregulation of B-cell receptor signaling and additional unique transcriptional programs. Leukemia 29:2270-3|
|Blonska, Marzenna; Agarwal, Nitin K; Vega, Francisco (2015) Shaping of the tumor microenvironment: Stromal cells and vessels. Semin Cancer Biol 34:3-13|
|Qu, Changju; Liu, Yadong; Kunkalla, Kranthi et al. (2013) Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-?B activation in diffuse large B-cell lymphoma. Blood 121:4718-28|
|Agarwal, Nitin K; Qu, Changju; Kunkalla, Kranthi et al. (2013) Transcriptional regulation of serine/threonine protein kinase (AKT) genes by glioma-associated oncogene homolog 1. J Biol Chem 288:15390-401|
|Kunkalla, Kranthi; Liu, Yadong; Qu, Changju et al. (2013) Functional inhibition of BCL2 is needed to increase the susceptibility to apoptosis to SMO inhibitors in diffuse large B-cell lymphoma of germinal center subtype. Ann Hematol 92:777-87|
|Greaves, Wesley; Xiao, Lianchun; Sanchez-Espiridion, Beatriz et al. (2012) Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols. J Hematol Oncol 5:47|
|Ramirez, Elisa; Singh, Rajesh R; Kunkalla, Kranthi et al. (2012) Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma. Leuk Res 36:1267-73|
|Ok, Chi Young; Singh, Rajesh Ramachandra; Vega, Francisco (2012) Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. Am J Pathol 180:2-11|
|Greaves, Wesley O; Kim, Ji Eun; Singh, Rajesh R et al. (2011) Glioma-associated oncogene homologue 3, a hedgehog transcription factor, is highly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma. Hum Pathol 42:1643-52|
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