兒童急性骨髓性白血病為什麼難治

04-26

（圖片說明：一個小男孩為了替自己患白血病的朋友募款而剃了一個光頭。）

最近寫研究經費申請，有感於兒童急性骨髓性白血病的難治，先說明一下文獻出處，來自2018年1月的Nature Medicine.

摘要如下，測了接近一千例兒童病人的基因組，著實是大手筆。

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in

Children』s Oncology Group (COG) AML trials. The COG–National Cancer Institute (NCI) TARGET AML initiative assessed cases

by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants

corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic

structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent

in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were

conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in

MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation

convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger–encoding

genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored

targeted therapies for the treatment of pediatric AML.

兒童跟成人病人相比，基因突變的分布很不一樣，見下圖，藍色是兒童，紅色是成人：

另外一點，兒童(TARGET AML)與成人(TCGA AML)相比，驅動白血病的基因突變(driver mutation)和融合基因(fusion gene, 粉色標識)分布相差也非常大：

作者最後感嘆，因為發病的分子機制不一樣，難怪適用於成人急性骨髓性白血病的化療藥物放在兒童病人上使用效果不好。