Detection of leukemogenic and paraleukemic target genes for childhood leukemic chimeric transcription factor

• Project/Area Number: 23591549
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Dokkyo Medical University
• Principal Investigator: HIDEMITSU Kurosawa 獨協医科大学, 医学部, 教授 (10205239)
• Research Collaborator: KIKUCHI Jiro ; FURUKAWA Yusuke ; INUKAI Takeshi ; INABA Toshiya
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 小児白血病 / PTHｒP / E2A-HLF / アポトーシス / PTHrP / 急性リンパ性白血病 / 高カルシウム血症 / apoptosis / PTHR-1 / PTHR1

Outline of Final Research Achievements

The E2A-HLF fusion transcription factor generated by t(17;19)(q22;p13) translocation is found in pro-B cell acute lymphoblastic leukemias (ALLs) and promotes leukemogenesis via antiapoptotic function, bone invasion, hypercalcemia and coagulopathy. Here, we demonstrate that t(17;19)+ ALL cells express PTHrP at high levels when compared with other ALL cells. Forced expression of E2A-HLF in t(17;19)- ALL cells up-regulated PTHrP expression, while transactivation domain mutants of E2A or basic domain mutants of HLF did not show PTHrP expression in t(17;19)- ALL cells. These results suggest that PTHrP is a downstream target of E2A-HLF. PTHrP knockdown by the shRNA lentivirus system induced sub-G0G1 and G0G1 accumulation indicating apoptosis in t(17;19)+ ALL cells. These data indicate that PTHrP expression, which is induced by E2A-HLF, is a key element in the protection of t(17;19)+ ALL cells from apoptosis and in the induction of bone invasion and hypercalcemia.

Research Products

• [Journal Article] Transplantation for juvenile myelomonocytic leukemia: a retrospective study of 30 children treated with a regimen of busulfan, fludarabine, and melphalan. (2015)
  • Author(s): Yabe H, Kurosawa H, et al.
  • Journal Title: Int J Hematol Volume: 101 Issue: 2 Pages: 184-190
  • DOI: 10.1007/s12185-014-1715-7
  • Peer Reviewed
• [Journal Article] Necessary stem cell transplantation using myeloablative therapy for myelodysplastic syndrome with progression of genotypic abnormalities and TP53 dysfunction in a young adult. (2014)
  • Author(s): Sato Y, Kurosawa H, et al.
  • Journal Title: Pediatr Transplant Volume: 18 Issue: 7
  • DOI: 10.1111/petr.12334
  • Peer Reviewed
• [Journal Article] Salvage allogeneic stem cell transplantation in patients with pediatric myelodysplastic syndrome and myeloproliferative neoplasms. (2014)
  • Author(s): Kato M, Kurosawa H, et al.
  • Journal Title: Pediatr Blood Cancer Volume: 61 Issue: 10 Pages: 1860-1866
  • DOI: 10.1002/pbc.25121
  • Peer Reviewed / Open Access
• [Journal Article] Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia. (2014)
  • Author(s): Koyama D, Kikuchi J, Hiraoka N, Wada T, Kurosawa H, Chiba S, and Furukawa Y.
  • Journal Title: Leukemia Volume: in press Issue: 6 Pages: 1216-1226
  • DOI: 10.1038/leu.2013.366
  • Peer Reviewed / Open Access
• [Journal Article] Myeloid leukemia発症18か月後にMLL/AF9陽性急性単球性白血病と診断した男児例． (2013)
  • Author(s): 佐藤雄也、中澤温子、黒澤秀光、福島啓太郎、奥谷真由子、萩沢進、杉田憲一、有阪治
  • Journal Title: 臨床血液 Volume: 54 Pages: 2167-2167
  • Peer Reviewed
• [Presentation] 17;19転座急性リンパ性白血病の抗アポトーシスと高カルシウム血症はE2A-HLFにより誘導されたPTHrPが関与している (2015)
  • Author(s): 黒澤秀光他
  • Organizer: 第24回癌病態治療研究会
  • Place of Presentation: 栃木県日光市
  • Year and Date: 2015-05-25
• [Presentation] Inhibitor of apoptosis protein family gene expression in childhood acute myeloid leukemia (AML). (2014)
  • Author(s): Kurosawa H, Sato Y, Okuya M, Fukushima K, Arisaka O, Park MJ, Matsui H, Inaba T, Inukai T, Fujimoto J, Tawa A, Tomizawa D, Taga T, Adachi S, Horibe K, Hayashi Y
  • Organizer: 第55回日本小児血液・がん学会
  • Place of Presentation: 福岡県福岡市
• [Presentation] Leukostasis in children and adolescents with CML: Japanese Pediatric Leukemia/Lymphoma Study Group. (2014)
  • Author(s): Kurosawa H, Tanizawa A, Tono C, Watanabe A, Shima H, Ito M, Yuza Y, Hotta N, Muramatsu H, Okada M, Kajiwara R, Saito A, Adachi S, Horibe K, Shimada H
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 北海道札幌市