Identification of new therapeutic target for MLL rearranged acute myeloid leukemia

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591547
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: IMAMURA Toshihiko 京都府立医科大学, 医学(系)研究科(研究院), 講師 (30444996)
• Project Period (FY): 2011 – 2013
• Keywords: AML / ATRA / LSD1 / H3K4me2 / MLL

Research Abstract

This study revealed the potential mechanism of high ATRA sensitivity of MLL-AF9-positive AML compared to MLL-AF4-positive AML. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARA gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1 +24/+25 intronic enhancer was higher in MLL-AF9-positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1 (LSD1), which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cell. These findings suggest that the level of H3K4me2 in the RARA gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML.

Research Products

• [Journal Article] Sensitivity of MLL-rearranged AML cells to all-transretinoic acid is associated with the level of H3K4me2 in the RARαpromoter region (2014)
  • Author(s): Sakamoto K, Imamura T, Yano M, Yoshida H, Fujiki A, Hirashima Y, Hosoi H.
  • Journal Title: Blood Cancer Journal Volume: 4 Pages: e205
  • DOI: 10.1038/bcj.2014.25
  • Peer Reviewed
• [Journal Article] Post-transcriptional modulation of C/EBPαprompts monocytic differentiation and apoptosis in acute myelomonocytic leukaemia cells (2012)
  • Author(s): Yoshida H, Imamura T, Fujiki A, Hirashima Y, Miyachi M, Inukai T, Hosoi H.
  • Journal Title: Leuk Res Volume: 36 Pages: 735-741
  • Peer Reviewed
• [Journal Article] All-trans retinoic acid combined with 5-Aza-2'-deoxycitidine induces C/EBPαexpression and growth inhibition in MLL-AF9-positive leukemic cells (2012)
  • Author(s): Fujiki A, Imamura T, Sakamoto K, Kawashima S, Yoshida H, Hirashima Y, Miyachi M, Yagyu S, Nakatani T, Sugita K, Hosoi H.
  • Journal Title: Biochem Biophys Res Commun Volume: 428 Pages: 216-223
  • Peer Reviewed
• [Presentation] MLL-AF9 positive acute myeloid leukemia cells are sensitive to all-trans retinoic acid (2013)
  • Author(s): Sakamoto K, Imamura T, Yano M, Yoshida H, Fujiki A, Hirashima Y, Hosoi H.
  • Organizer: 55th ASH Annual Meeting and Exposition
  • Place of Presentation: New Orleans, LA, U.S.A
  • Year and Date: 20131207-10
• [Presentation] MLL-AF9陽性急性骨髄性白血病細胞はATRA感受性を示す (2013)
  • Author(s): 坂本謙一,今村俊彦,矢野未央,吉田秀樹,藤木敦,平嶋良章,細井創
  • Organizer: 第55回日本小児血液・がん学会
  • Place of Presentation: 福岡
  • Year and Date: 20131129-1201
• [Presentation] LSD1 inhibitor activates retinoic acid pathway in MLL fusion positive acute myeloid leukemia (2012)
  • Author(s): Yano M, Imamura T, Sakamoto K, Yoshida H, Fujiki A, Hirashima Y, Ishida H, Hosoi H.
  • Organizer: 54th ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta, GA, U.S.A
  • Year and Date: 20121208-11
• [Presentation] LSD1阻害薬はMLL融合遺伝子陽性急性骨髄性白血病においてレチノイン酸受容体経路の活性化を誘導する (2012)
  • Author(s): 矢野未央,今村俊彦,坂本謙一,吉田秀樹,藤木敦,平嶋良章,石田宏之,細井創
  • Organizer: 第54回日本小児血液・がん学会
  • Place of Presentation: 横浜
  • Year and Date: 20121130-1202
• [Presentation] MLL fusion partners affect the sensitivity of human and murine leukemic cell lines to DNMTi (2011)
  • Author(s): Fujiki A, Imamura T, Yoshida H, Hirashima Y, Miyachi M, Yagyu S, Nakatani T, Hosoi H.
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋
  • Year and Date: 20111014-16