Study on mechanism and alteration of ATRA-resistance caused by mutant PML-RARα in acute promyelocytic leukemia

• Project/Area Number: 15591081
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: TOHOKU UNIVERSITY
• Principal Investigator: FUJII Kunihiro (2004) Tohoku University, Hospital, Research Associate, 病院, 助手 (20344674); 今泉 益栄 (2003) 東北大学, 大学院・医学系研究科, 助教授 (40191895)
• Co-Investigator(Kenkyū-buntansha): SUGAWARA Akira Tohoku University, Hospital, Lecturer, 病院・講師 (90270834) ; TANAKA Takashi Tohoku University, Hospital, Research Associate, 病院・助手 (10292335) ; 藤井 邦裕 東北大学, 医学部附属病院, 助手 (20344674) ; 佐藤 篤 東北大学, 医学部附属病院, 助手 (20292336)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
• Keywords: Acute promyelocytic leukemia / mutant PML-RARa / ATRA-resistance / Am80 / Am80 / PML / MRDモニタリング / FLT3遺伝子 / 急性前骨髄球性白血病 / 変異PML-RARα / 分子標的療法 / アポトーシス

Research Abstract

Study on ATRA-resistance caused by mutant PML-RAR α ; In this study, we examined the cellular and molecular RA-response of a human APL cell line, UF-1, established from a patient who had ATRA-resistance and a mutation in the PML-RAR α chimeric protein. For cellular RA-response, differentiation and apoptosis was evaluated in UF-1 cells treated with retinoids. For molecular RA-response, RA-dependent transcriptional activity of PML-RARa chimeric protein and RT-PCR of PML-RAR α, RAR α, RAR β, and RAR γ was determined. In response to ATRA and Am80 at 100 nM or lower doses, neither cellular nor molecular RA-response was detected. By contrast, in response to 1 □M ATRA and Am80, UF-1 showed a full-scaled maturation with apoptosis, whereas molecular RA-response of the mutant PML-RARa was insufficient. These findings suggest that the dose-dependently altered ATRA-response of UF-1 cells may be determined through the interaction between the mutant PML-RARa and other intrinsic nuclear RA receptors.

Research Products

• [Journal Article] Alteration in the cellular response to retinoic acid of a human acute promyelocytic leukemia cell line, UF-1, carrying a patient-derived mutant PML-RARalpha chimeric gene. (2004)
  • Author(s): Atsushi Sato
  • Journal Title: Leukemia Research 28(9) Pages: 959-967
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sato A, Imaizumi M et al.: "Alteration in the cellular response to retinoic acid of a human acute promyelocytic leukemia cell line, UF-1, carrying a patient-derived mutant PML-RARα chimeric gene"Leukemia Reserch. (in press). (2004)
• [Publications] Imaizumi M: "Differentiation-induction therapy with all-trans retinoic acid (ATRA) for acute promyelocytic leukemia : Involvement of mutant PML-RAR_in ATRA resistance"Recent Res Devel Haematol. (in press). (2004)
• [Publications] Xu G, Nagano M et al.: "Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down's syndrome"Blood. 102. 2960-2968 (2003)
• [Publications] Kudo Y, Minegishi M et al.: "The absolute number of peripheral blood CD34+ cells predicts a timing for apheresis and progenitor cell yield in patients with hematologic malignancies and solid tumors"Tohoku J Exp Med. 199. 111-118 (2003)