The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors
The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors
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DOI：
10.1038/s41467-018-07846-y
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发表时间：
2019-01-04
影响因子：
16.6
通讯作者：
Cancelas, J. A.
中科院分区：
文献类型：
--
作者：
Nayak, R. C.;Hegde, S.;Cancelas, J. A.
表观遗传调控的转录可塑性被认为是分化、阻滞和抗治疗的一种机制。BCR-ABL白血病是白血病干细胞/祖细胞转化的结果，是鉴定谱系白血病发生的表观遗传过程的一个机会。原代人和小鼠BCR-ABL（+）白血病祖细胞Cdc42和下游非典型蛋白激酶C （aPKC）的活化增加。虽然aPKC zeta亚型表现为白血病抑制因子，但aPKC lambda/iota对致癌祖细胞增殖、存活和b细胞分化抑制至关重要，但对正常b细胞谱系分化不重要。体外和体内BCR-ABL转化b细胞需要通过aPKC lambda/iota-Erk依赖的Etv5/Satb2染色质抑制信号复合体下调b细胞分化程序中的关键基因。遗传或药理学靶向aPKC损害人类致癌成瘾白血病。因此，aPKC lambda/iota-SATB2信号级联是白血病BCR-ABL(+) b细胞祖细胞转化所必需的，并且可受非酪氨酸激酶抑制。
Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL(+) leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKC zeta behaves as a leukemic suppressor, aPKC lambda/iota is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC lambda/iota-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKC lambda/iota-SATB2 signaling cascade is required for leukemic BCR-ABL(+) B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition.