发明名称 |
Recurrent mutations in epigenetic regulators, <i>RHOA </i>and <i>FYN </i>kinase in peripheral T-cell lymphomas |
摘要 |
Whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing identified new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DN-MT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, new and recurrent, genetic defects are described including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL. |
申请公布号 |
US9574241(B2) |
申请公布日期 |
2017.02.21 |
申请号 |
US201414895287 |
申请日期 |
2014.06.03 |
申请人 |
The Trustees of Columbia University in the City of New York |
发明人 |
Ferrando Adolfo;Rabadan Raul;Palomero Teresa |
分类号 |
A61K31/497;C12Q1/68;A61K31/506 |
主分类号 |
A61K31/497 |
代理机构 |
Beusse Wolter Sanks & Maire |
代理人 |
Evans Judith A.;Beusse Wolter Sanks & Maire |
主权项 |
1. A method, comprising
(a) providing a biological sample from a subject that has lymphoma; (b) analyzing the biological sample to detect for presence of RHOA p.Glyl7Val mutation, (c) determining that the subject has Peripheral T-Cell Lymphoma if RHOA p.Glyl7Val mutation, is detected in the biological sample and (d) if it is determined that the subject has an increased risk of developing Peripheral T-Cell Lymphoma due to the presence of a mutation selected from the group consisting of FYN p.Leu174Arg, FYN p.Arg176Cys, and FYN p.Tyr531His, then prophylactically treating the subject for Peripheral T-Cell Lymphoma by administering a therapeutically effective amount of an SRC kinase inhibitor. |
地址 |
New York NY US |