Mechanisms of resistance against histone deacetylase inhibitors in refractory lymphoid malignancies

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591406
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Nagoya City University
• Principal Investigator: IIDA SHINSUKE 名古屋市立大学, 医学(系)研究科(研究院), 教授 (50295614)
• Co-Investigator(Kenkyū-buntansha): RI Masaki 名古屋市立大学, 大学院医学研究科, 助教 (00567539)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 医療 / がん / 薬剤耐性 / リンパ腫 / 骨髄腫 / HDAC阻害剤

Outline of Final Research Achievements

Histone deacetylase inhibitor (HDACI) has been demonstrated to be effective for the patients with cutaneous T-cell lymphoma (CTCL) and multiple myeloma (MM). To elucidate the mechanisms of acquired resistance against HDACI in these tumors, we established various vorinostat-resistant cell lines. Comparison between these resistant and their parental cell lines has shown the following differences. Pan-HDAC activity was generally low in HDACI-resistant cells, but reduced HDAC3 activity was commonly shared in HDACI-resistant cell lines. Reduced expression of HDAC3 by shRNA decreases the sensitivity to HDACI, whereas that of other HDACs do not. Neither genetic mutation nor promoter methylation exists in HDAC3 gene in HDACI-resistant cells. Thus, reduced expression of HDAC3 is responsible for the acquired resistance against HDACI in part, although the underlying mechanism remains to be clarified.

Free Research Field

血液・腫瘍学