Identification of new therapeutic target for MLL rearranged acute myeloid leukemia

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: AML / ATRA / LSD1 / H3K4me2 / MLL / C/EBPA / 分化誘導 / LSD1阻害剤 / mTOR阻害剤 / RARA / 急性骨髄性白血病 / レチノイン酸 / MLL遺伝子 / 分化誘導療法

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 (2014)
  • Author(s): Sakamoto K, Imamura T, Yano M, Yoshida H, Fujiki A, Hirashima Y, Hosoi H
  • Journal Title: Blood Cancer Journal Volume: 4 Issue: 4 Pages: 205-205
  • 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
• [Journal Article] Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003–06 from the Japan Association of Childhood Leukaemia Study. (2012)
  • Author(s): Imamura T, Adachi S, et al.
  • Journal Title: British Journal of Haematology Volume: 159 Issue: 2 Pages: 204-210
  • DOI: 10.1111/bjh.12030
  • Peer Reviewed
• [Journal Article] All-trans retinoic acid combined with 5-Aza-2'-deoxycitidine induces C/EBPα expression 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 Issue: 2 Pages: 216-223
  • DOI: 10.1016/j.bbrc.2012.09.131
  • Peer Reviewed
• [Journal Article] Quantitative RT-PCR analysis of the MOZ-CBP fusion transcript in therapy-related acute myeloid leukemia with t(8;16)(p11;p13). (2012)
  • Author(s): Fujiki A, Imamura T, Furutani A, Hatano W, Asai D, Hirashima Y, Miyachi M, Tamura S, Tsuchiya K, Iehara T, Ishida H, Yoshihara T, Hosoi H.
  • Journal Title: J Pediatr Hematol Oncol Volume: 34 Issue: 5 Pages: 402-405
  • DOI: 10.1097/mph.0b013e318238818f
  • Peer Reviewed
• [Journal Article] GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia (2012)
  • Author(s): Ishida H, Imai K, Homma K, Tamura S, Imamura T, Itoh M, Nonoyama S
  • Journal Title: Eur J Pediatr Volume: 171 Issue: 8 Pages: 1273-1276
  • DOI: 10.1007/s00431-012-1715-7
  • Peer Reviewed
• [Journal Article] Allo-SCT in a patient with CRMCC with aplastic anemia using a reduced intensity conditioning regimen. (2012)
  • Author(s): Asai D, Osone S, Imamura T, Sakaguchi H, Nishio N, Kuroda H, Kojima S, Hosoi H
  • Journal Title: Bone Marrow Transplant Volume: 47 Issue: 8 Pages: 1126-1127
  • DOI: 10.1038/bmt.2011.221
  • Peer Reviewed
• [Journal Article] Post-transcriptional modulation of C/EBPα prompts 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: Leukemia Research Volume: 36 Issue: 6 Pages: 735-741
  • DOI: 10.1016/j.leukres.2012.01.009
  • 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
• [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
• [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
• [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
• [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
• [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
• [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
• [Presentation] IKZF1 deletion is strongly associated with risk of relapse in pediatric B cell precursor ALL with TCF3-PBX1. (2012)
  • Author(s): Asai D, Imamura T, Suenobu S, Moriya Saito A, Hasegawa D, Deguchi T, Hashii Y, Endo M, Hatakeyama N, Kawasaki H, Hori H, Horibe K, Yagi K, Hara J, Oda M, Sato A.
  • Organizer: 54th ASH Annual Meeting and Exposition
  • Place of Presentation: Atlanta, GA, U.S.A
• [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
• [Presentation] Early T-cell precursor ALLにおける臨床および生物学的検討. (2012)
  • Author(s): 川島幸子, 今村俊彦, 中谷拓也, 平嶋良章, 田村真一, 大曽根眞也, 石田宏之, 森本 哲, 黒田啓史, 日比成美, 今宿晋作, 細井創.
  • Organizer: 第54回日本小児血液･がん学会
  • Place of Presentation: 横浜
• [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
• [Presentation] IKZF1 deletion is strongly associated with risk of relapse in intermediate risk group in JACLS ALL02 cohort. (2011)
  • Author(s): Asai D, Imamura T, Suenobu S, Hasegawa D, Deguchi T, Hashii Y, Matsumoto K, Kawasaki H, Hori H, Iguchi A, Kosaka Y, Kato K, Horibe K, Yagi K, Hara J, Oda M.
  • Organizer: 53rd ASH Annual Meeting and Exposition
  • Place of Presentation: San Diego, CA, U.S.A.