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Kutok, Jeffery Lorne

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Kutok

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Jeffery Lorne

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Kutok, Jeffery Lorne

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2010 - 20122

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Author's Publications: search.filters.isAuthorOfPublication.79c1dc00-32f4-40a2-b6f9-16ecdfaa3d47

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    T-Lymphoblastic Lymphoma Cells Express High Levels of BCL2, S1P1, and ICAM1, Leading to a Blockade of Tumor Cell Intravasation
    (Elsevier BV, 2010) Feng, Hui; Stachura, David L.; White, Richard; Gutierrez, Alejandro; Zhang, Lu; Sanda, Takaomi; Jette, Cicely A.; Testa, Joseph R.; Neuberg, Donna; Langenau, David; Kutok, Jeffery Lorne; Zon, Leonard; Traver, David; Fleming, Mark; Kanki, John P.; Look, A.
    The molecular events underlying the progression of T-lymphoblastic lymphoma (T-LBL) to acute T-lymphoblastic leukemia (T-ALL) remain elusive. In our zebrafish model, concomitant overexpression of bcl-2 with Myc accelerated T-LBL onset while inhibiting progression to T-ALL. The T-LBL cells failed to invade the vasculature and showed evidence of increased homotypic cell-cell adhesion and autophagy. Further analysis using clinical biopsy specimens revealed autophagy and increased levels of BCL2, S1P1, and ICAM1 in human T-LBL compared with T-ALL. Inhibition of S1P1 signaling in T-LBL cells led to decreased homotypic adhesion in vitro and increased tumor cell intravasation in vivo. Thus, blockade of intravasation and hematologic dissemination in T-LBL is due to elevated S1P1 signaling, increased expression of ICAM1, and augmented homotypic cell-cell adhesion.
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    Autocrine Activation of the MET Receptor Tyrosine Kinase in Acute Myeloid Leukemia
    (Nature Publishing Group, 2012) Kentsis, Alex; Reed, Casie; Rice, Kim L.; Sanda, Takaomi; Rodig, Scott; Tholouli, Eleni; Christie, Amanda; Valk, Peter J.M.; Delwel, Ruud; Ngo, Vu; Kutok, Jeffery Lorne; Dahlberg, Suzanne E.; Moreau, Lisa A.; Byers, Richard J.; Christensen, James G.; Woude, George Vande; Licht, Jonathan D.; Kung, Andrew L.; Staudt, Louis M.; Look, A.
    Although the treatment of acute myeloid leukemia (AML) has improved significantly, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified aberrant expression of the hepatocyte growth factor (HGF) as a critical factor in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance due to compensatory upregulation of HGF expression, leading to restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked compensatory HGF upregulation, resulting in sustained logarithmic cell kill both in vitro and in xenograft models in vivo. Our results demonstrate widespread dependence of AML cells on autocrine activation of MET, as well as the importance of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers.