The molecular mechanism that ATRA induces granulocytic differentiation in leukemic cells through the protein acetylation

• Project/Area Number: 26893264
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Juntendo University
• Principal Investigator: SUNAMI YOSHITAKA 順天堂大学, 医学部, 助教 (50732864)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PCAF / 急性前骨髄球性白血病(APL) / 全トランスレチノイン酸(ATRA) / 分化誘導療法 / ヒストンアセチル基転移酵素 / 蛋白質アセチル化 / 急性前骨髄球性白血病 / ATRA / 好中球分化 / 全トランスレチノイン酸 / 分化誘導

Outline of Final Research Achievements

All-trans retinoic acid (ATRA) induces granulocytic differentiation in acute promyelocytic leukemia (APL) cells, however, its detailed molecular mechanism remains unclear. Here, we showed that the overexpression of a histone acetyltransferase PCAF induced the expression of the granulocytic differentiation marker at the mRNA level, suggesting that PCAF is essential for APL cell differentiation. In addition, we found that ATRA acetylated the PCAF substrates while ATRA induced granulocytic differentiation in leukemic cells. Furthermore, PCAF regulated the downstream target gene expression of ATRA. These observations suggested that ATRA induced granulocytic differentiation in APL cells through the PCAF-induced protein acetylation and the PCAF-regulated downstream target gene expression.

Research Products

• [Journal Article] Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. (2016)
  • Author(s): Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N
  • Journal Title: Blood Volume: 127 Issue: 10 Pages: 1307-16
  • DOI: 10.1182/blood-2015-09-671172
  • Peer Reviewed / Open Access
• [Journal Article] Melting curve analysis after T allele enrichment (MelcaTle) as a highly sensitive and reliable method for detecting the JAK2V617F mutation. (2015)
  • Author(s): Morishita S, Takahashi K, Araki M, Hironaka Y, Sunami Y, Edahiro Y, Tsutsui M, Ohsaka A, Tsuneda S, Komatsu N.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0122003-e0122003
  • DOI: 10.1371/journal.pone.0122003
  • Peer Reviewed / Open Access
• [Journal Article] Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia. (2015)
  • Author(s): Shirane S, Araki M, Morishita S, Edahiro Y, Sunami Y, Hironaka Y, Noguchi M, Koike M, Sato E, Ohsaka A, Komatsu N.
  • Journal Title: Int J Hematol Volume: 101 Issue: 2 Pages: 148-53
  • DOI: 10.1007/s12185-014-1721-9
  • Peer Reviewed
• [Journal Article] JAK2, CALR, and MPL mutation status in Japanese myeloproliferative neoplasms patients (2015)
  • Author(s): Shirane S, Araki M, Morishita S, Edahiro Y, Sunami Y, Hironaka Y, Noguchi M, Koike M, Ohsaka A, and Komatsu N
  • Journal Title: Haematologica Volume: 100 Issue: 2 Pages: e46-e48
  • DOI: 10.3324/haematol.2014.115113
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay (2014)
  • Author(s): Takei H, Morishita S, Araki M, Edahiro Y, Sunami Y, Hironaka Y, Noda N, Sekiguchi Y, Tsuneda S, Ohsaka A, and Komatsu N
  • Journal Title: PLoS ONE Volume: 9 Issue: 8 Pages: e104958-e104958
  • DOI: 10.1371/journal.pone.0104958
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rituximab plus a CHOP-like regimen, central nervous system prophylaxis, and contralateral testicular irradiation for localized primary testicular diffuse large B-cell lymphoma lead to prolonged progression-free survival. (2014)
  • Author(s): Ichikawa K, Noguchi M, Koike M, Aritaka N, Sekiguchi Y, Sunami Y, Tsutsui M, Hosone M, Hirano T, Gotoh A, Komatsu N
  • Journal Title: Int J Hematol Volume: 100 Issue: 4 Pages: 370-8
  • DOI: 10.1007/s12185-014-1646-3
  • Peer Reviewed
• [Journal Article] JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan (2014)
  • Author(s): EdahiroY, Morishita S, Takahashi K, Hironaka Y, Yahata Y, Sunami Y, Shirane S, Tsutsui M, Noguchi M, Koike M, Imai K, Noda N, Sekiguchi Y, Tsuneda S, Ohsaka A, Araki M, Komatsu N
  • Journal Title: Int J Hematol Volume: 99(5) Issue: 5 Pages: 625-634
  • DOI: 10.1007/s12185-014-1567-1
  • Peer Reviewed
• [Presentation] Activation of AP-1 By JAK2V617F through Induction and Stabilization of c-FOS (2015)
  • Author(s): Araki M, Edahiro Y, Yang Y, Hironaka Y, Morishita S, SunamiY, Ohsaka A, Komatsu N
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: Orland
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Isolation of all-trans retinoic acid-response element on PCAF promoter. (2015)
  • Author(s): Sunami Y, Araki M, Pyanuch S, Shin K, Ito A, Hironaka Y, Ohsaka A, Yoshida M, Komatsu N
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Involvement of histone acetyltransferases is development of acute promyelocytic leukemia and response to differentiation-inducing compound. (2015)
  • Author(s): Sunami Y, Araki M, Ito A, Hironaka Y, Ohsaka A, Yoshida M, Komatsu N.
  • Organizer: 20th Congress of the European Hematology Association
  • Place of Presentation: Vienna
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] Histone acetyltransferase PCAF is required for ATRA-induced granulocytic differentiation in acute promyelocytic leukemia cells. (2014)
  • Author(s): Sunami Y, Araki M, Ito A, Hironaka Y, Ohsaka A, Yoshida M, Komatsu N.
  • Organizer: 56th Annual Meeting of the ASH
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-06
  • Int'l Joint Research
• [Presentation] ATRA induces APL cell granulocytic differentiation through the PCAF overexpression. (2014)
  • Author(s): Sunami Y, Araki M, Ito A, Hironaka Y, Ohsaka A, Yoshida M, Komatsu N.
  • Organizer: 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31
• [Presentation] Establishment of a novel assay for MPLW515/K detection and allele burden measurement (Japanese). (2014)
  • Author(s): Takei H, morishita S, Araki M, Edahiro Y, Sunami Y, Hironaka Y, Noda N, Sekiguchi Y, Tsuneda S, Ohsaka A, Komatsu N.
  • Organizer: 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31
• [Presentation] Establishment of acute erythroid leukemia cell line, EL-1. (2014)
  • Author(s): Tsutsui M, Araki M, Sunami Y, Hironaka Y, Ohsaka A.
  • Organizer: 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31
• [Presentation] JaK2V617F allele burden is a potential prognostic factor for the transformation into myelofibrosis. (2014)
  • Author(s): Shirane S, Araki M, Morishita S, Edahiro Y, Sunami Y, Hironaka Y, Ohsaka A, Komatsu N.
  • Organizer: 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31
• [Presentation] MPL mutation analysis of Ph-negative myeloproliferative neoplasms in Japan. (2014)
  • Author(s): Edahiro Y, Shirane S, Takei H, morishita S, Sunami Y, Hironaka Y, Tsuneda S, Ohsaka A, Araki M, Komatsu N.
  • Organizer: 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-10-31
• [Presentation] Histone acetyltransferase PCAF is required for ATRA-induced granulocytic differentiation in APL cells. (2014)
  • Author(s): Sunami Y, Araki M, Ito A, Hironaka Y, Ohsaka A, Yoshida M, Komatsu N.
  • Organizer: 35th World Congress of the International Society of Hematology.
  • Place of Presentation: Beijing, China
  • Year and Date: 2014-09-04
  • Int'l Joint Research
• [Book] BIO Clinica (2014)
  • Author(s): 筒井深雪、角南義孝、小松則夫
  • Total Pages: 104
  • Publisher: 北陸館