The Overexpression of ABCG2 Reduces the Efficacy of Volasertib (BI 6727) and GSK641364 in Human S1-M1-80 Colon Carcinoma Cells
Pages 108-116
Sung-Han Hsiao, Shi-Yu Luo, Ching-Ya Su, Wei-Cherng Tuo, Cheng-Ting Chiang, Yan-Qing Li, Yang-Hui Huang and Chung-Pu Wu

DOI: http://dx.doi.org/10.6000/1929-2279.2014.03.02.5

Published: 08 May 2014

Abstract: The polo-like kinase 1 (Plk1) is one of the key regulators in cell cycle progression. Plk1 is overexpressed in many types of cancer and promotes the proliferation of cancer cells. Inhibition of Plk1 activity induces G2/M cell cycle arrest and reduces cancer cell viability. Volasertib and GSK461364 are selective inhibitors of Plk1, active against a wide range of tumor cells at nanomolar concentrations. In this study, while examining the effectiveness of Plk1 inhibitors against multiple human colon cancer cell lines, we discovered that the overexpression of ATP-binding cassette (ABC) drug transporter ABCG2 in human S1-M1-80 colon cancer cells confers resistance to volasertib and GSK461364. Moreover, we found that ABCG2-transfected HEK293 cells were also resistant to both Plk1 inhibitors. We revealed that volasertib and GSK461364 inhibited the function of ABCG2 in a concentration dependent manner, and had no significant effect on the protein expression of ABCG2. More importantly, we showed that the G2/M cell cycle arrest induced by volasertib or GSK461364 was significantly reduced in S1-M1-80 cells, and that ABCG2-mediated drug resistance to Plk1 inhibitors can be restored by inhibition of ABCG2 function. Therefore, the development of ABCG2-mediated drug resistance to volasertib and GSK461364 in cancer clearly present a significant therapeutic challenge, and a better treatment strategy should be further investigated.

Secondary Precursor T-Cell Lymphoblastic Lymphoma Following Precursor B-cell Acute Lymphoblastic Leukemia: A Case Report and Review of the Literature
Pages 117-122
Jenny L. Smith, Albert Kheradpour, Craig W. Zuppan, Jun Wang, Rhett P. Ketterling and Edward H. Rowsell

DOI: http://dx.doi.org/10.6000/1929-2279.2014.03.02.6

Published: 08 May 2014

Abstract: Although relapse of lymphoma/leukemia is not uncommon, sequential development of a second lymphoma/leukemia of a different cell lineage is rare. We report the case of a 3-year-old girl who initially presented with precursor B-cell acute lymphoblastic leukemia (B-ALL), characterized by a cryptic t(12;21) with associated ETV6/RUNX1 fusion, an 11q (MLL) deletion, and a balanced inv(2)(q31q37). She was successfully treated but five years later developedthymicprecursor T-cell lymphoblastic lymphoma (T-LBL) expressing a completely different phenotypic profile. Fluorescence in situ hybridization testing identified a MLL rearrangement but indicated no ETV6/RUNX1 fusion. Although the marrow was uninvolved, aspirates evaluated by chromosome studies revealed the same inv(2q), suggesting a constitutional abnormality distinct from the somatic alterations associated with her B-ALL and T-LBL. This raisesthe possibilityof a potential tumor suppressor gene or proto-oncogene residing in the region of the inversion breakpoints which could contribute to predisposition to the development of lymphoblastic leukemias/lymphomas. While secondary leukemia may emerge as a therapy-related process and the presence of an MLL rearrangement in the T-LBL represents an interesting abnormality in this regard,athymicpresentation would be exceedingly unusual. To our knowledge, this is the first reported case of B-ALL followed by an apparently genetically unrelatedT-LBL.