2021 Fiscal Year Final Research Report
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 |
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) |
Principal Investigator |
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | 急性前骨髄急性白血病 / RARB / retinoic acid pathway |
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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Free Research Field |
小児がん
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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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