Crosstalk between hnRNP K and SET in ATRA-induced differentiation in acute promyelocytic leukemia.
Crosstalk between hnRNP K and SET in ATRA-induced differentiation in acute promyelocytic leukemia.
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DOI：
10.1002/2211-5463.13210
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发表时间：
2021-07
期刊：
影响因子：
2.6
通讯作者：
Leopoldino AM
中科院分区：
文献类型：
--
作者：
Padovani KS;Goto RN;Fugio LB;Garcia CB;Alves VM;Brassesco MS;Greene LJ;Rego EM;Leopoldino AM
HnRNP K蛋白是一种异质核核糖核蛋白，已被认为参与急性早幼粒细胞白血病（APL）的白血病发生，以及全反式维甲酸（ATRA）诱导的分化。我们之前证明了SET和hnRNP K在头颈部鳞状细胞癌（HNSCC）细胞中与剪接加工相关的功能之间的联系。本研究的目的是表征hnRNP K和SET蛋白在ATRA诱导的APL分化中的参与。我们观察到APL患者在诊断期的hnRNP K和SET mRNA水平比诱导和维持期高（5 - 40倍）。使用短发夹RNA敲低hnRNP K导致ATRA敏感的NB4和耐药的NB4‐R2细胞凋亡，并伴有SET切割。此外，hnRNP K敲低增加了APL细胞的粒细胞分化，主要是在NB4‐R2与ATRA中。hnRNP K敲除的效果与U0126（一种减数分裂特异性丝氨酸/苏氨酸蛋白激酶/ERK抑制剂）处理的效果相似，主要在NB4‐R2细胞中。APL细胞中SET敲低表明，hnRNP K敲低的细胞通过SET切割而不是通过SET蛋白的减少诱导凋亡。将NB4‐R2细胞移植到裸鼠体内证实，与ATO相比，三氧化二砷（ATO）联合U0126具有更高的抑制肿瘤进展的潜力。因此，hnRNP K/SET和ERK是抗肿瘤性白血病治疗和ATRA耐药复发APL患者的潜在治疗靶点。ERK抑制或异质核核糖核蛋白K敲低会降低细胞活力，增加全反式维甲酸（ATRA）诱导的急性早幼粒细胞白血病（APL） ATRA抗性细胞的分化，并促进SET切割。此外，使用异种移植NB4‐R2肿瘤模型获得的研究结果表明，使用U0126（减数分裂特异性丝氨酸/苏氨酸蛋白激酶/ERK抑制剂）联合三氧化二砷作为APL的潜在治疗策略有待探索。我们的研究强调了APL中ERK/hnRNPK/SET与ATRA诱导的分化之间的串扰。
HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all‐trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA‐induced differentiation in APL. We observed higher (5‐ to 40‐fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short‐hairpin RNA led to cell death in ATRA‐sensitive NB4 and resistant NB4‐R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4‐R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis‐specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4‐R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4‐R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance. ERK inhibition or heterogeneous nuclear ribonucleoprotein K knockdown decreases cell viability, increases all‐trans retinoic acid (ATRA)‐induced differentiation in acute promyelocytic leukemia (APL) ATRA‐resistant cells, and promotes SET cleavage. Furthermore, findings obtained using a xenograft NB4‐R2 tumor model suggest the use of U0126, a meiosis‐specific serine/threonine protein kinase/ERK inhibitor, combined with arsenic trioxide as a potential therapeutic strategy to be explored for APL. Our study highlights crosstalk between ERK/hnRNPK/SET in APL and ATRA‐induced differentiation.
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影响因子：
3.5
作者：
Lam, B. Daniel;Anthony, Eloise C.;Hordijk, Peter L.
通讯作者：
Hordijk, Peter L.
DOI：
10.1016/j.bbrc.2015.01.104
发表时间：
2015-03-06
影响因子：
3.1
作者：
Almeida, Luciana O.;Goto, Renata N.;Leopoldino, Andreia M.
通讯作者：
Leopoldino, Andreia M.
DOI：
10.1016/j.bbrc.2014.01.175
发表时间：
2014-02-28
影响因子：
3.1
作者：
Almeida, Luciana O.;Garcia, Cristiana B.;Leopoldino, Andreia M.
通讯作者：
Leopoldino, Andreia M.
影响因子：
8
作者：
Evans, JR;Mitchell, SA;Willis, AE
通讯作者：
Willis, AE
影响因子：
11.4
作者：
AMATI, B;LITTLEWOOD, TD;LAND, H
通讯作者：
LAND, H