Elucidation of the pathophysiology of RARB translocation-positive acute promyelocytic leukemia and development of new target therapy
| Project/Area Number |
19K16762
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Yokohama City University (2020-2021)
National Center for Child Health and Development (2019) |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 急性前骨髄急性白血病 / RARB / retinoic acid pathway / 急性前骨髄球性白血病 / TBL1XR1-RARB / APL / レチノイン酸 |
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| Outline of Research at the Start |
急性前骨髄球性白血病患者から申請者らが同定したレチノイン酸受容体β(RARB)関連新規融合遺伝子の白血病発症に関わる役割の解明、さらなる症例の収集による発症頻度の評価・臨床像の把握、及びさらなるゲノム解析、新規標的薬剤の同定を行うことである。本研究は以下の要素から構成される。広く症例を収集しRARB関連融合遺伝子陽性白血病の頻度およびその臨床像を評価し、ゲノム解析を進め、RARB関連融合遺伝子と協調して白血病発症に関与するdriver mutationの同定を進める。新規融合遺伝子TBL1XR1-RARBの白血病発症機序に関わる知見をin vitro/in vivoの実験でさらに深める。
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| Outline of Final Research Achievements |
Almost all of Acute promyelocytic acute leukemia (APL) is caused by a translocation of the RARA gene, but in some cases this RARA translocation can not be identified. We recently identified RARB translocation as the recurrent genomic alteration in APL without RARA rearrangements. Howevere,the functional consequences of APL with RARB rearrangements are still unknown. Thus, we performed functional analyses of APL with RARB rearrangement. RARB rearrangement could make homodimerize and blocked retinoic acid pathway in dominant-negative manner. Furthermore, we showed that synthetic retinoids such as all-trans retinoic acid were ineffective for RARB rearrangement positive APL. As retinoids have insufficient therapeutic effects on APL with RARB rearrangement, we performed transcriptome analysis using RARB rearrangement induced cell line. We found TBL1XR1-RARB significantly suppressed the expression of PPARγ target genes, and PPARγ ligands could partially differentiate RARB rearrangements.
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| Academic Significance and Societal Importance of the Research Achievements |
急性前骨髄球性白血病（APL）は、ほとんどの症例でPML-RARAなどのRARA遺伝子関連の融合遺伝子を有し、オールトランス型レチノイン酸(ATRA)などの治療が有効である。しかし、一部のAPLの症例の中にこのRARA遺伝子関連の異常を有さない症例が存在する。我々は、これらの症例のゲノム解析を行い、新たにRARB遺伝子関連の異常を見出した。このRARB関連遺伝子を有するAPLは、RARA遺伝子異常を有するAPLと同様の病態で白血化をきたすことを示した。また、ATRAを始めとしたレチノイン酸は無効であり、PPARγに対する治療が有効であることを見出した。今後の治療応用が期待される。
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Report
(4 results)
Research Products
(7 results)
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[Journal Article] Genome-wide DNA Methylation Analysis in Pediatric Acute Myeloid Leukemia.2022
Author(s)
Yamato G, Kawai T, Shiba N, Ikeda J, Hara Y, Ohki K, Tsujimoto SI, Kaburagi T, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Taga T, Horibe K, Ogawa S, Hata K, Hayashi Y.
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Journal Title
Blood advances
Volume: in press
Issue: 11
Pages: 3207-3219
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Droplet digital polymerase chain reaction assay for the detection of the minor clone of KIT D816V in paediatric acute myeloid leukaemia especially showing RUNX1-RUNX1T1 transcripts.2021
Author(s)
Sasaki K, Tsujimoto S, Miyake M, Uchiyama Y, Ikeda J, Yoshitomi M, Shimosato Y, Tokumasu M, Matsuo H, Yoshida K, Ohki K, Kaburagi T, Yamato G, Hara Y, Takeuchi M, Kinoshita A, Tomizawa D, Taga T, Adachi S, Tawa A, Horibe K, Hayashi Y, Matsumoto N, Ito S, Shiba N.
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Journal Title
British Journal of Haematology
Volume: 194(2)
Issue: 2
Pages: 414-422
DOI
Related Report
Peer Reviewed
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