GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML
GADD45g acts as a novel tumor suppressor, and its activation suggests new combination regimens for the treatment of AML
复制标题
GADD45g 作为一种新型肿瘤抑制因子，其激活为治疗 AML 提供了新的联合方案。
DOI：
10.1182/blood.2020008229
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发表时间：
2021-08-12
期刊：
影响因子：
20.3
通讯作者：
Ma, Xiaotong
中科院分区：
文献类型：
--
作者：
Guo, Dan;Zhao, Yangyang;Ma, Xiaotong
急性髓性白血病（AML）是一种侵袭性造血系统恶性肿瘤，对新的治疗策略的需求尚未得到满足。在这里，我们的特点是生长停滞和DNA损伤诱导基因γ（GADD 45 g）作为一种新的肿瘤抑制剂在AML。我们发现GADD 45 g在AML中优先沉默，特别是在伴有FMS样酪氨酸激酶3-内部串联重复（FLT 3-ITD）突变和混合系白血病（MLL）重排的AML中，GADD 45 g表达减少与AML患者的不良预后相关。GADD 45 g的上调损害同源重组DNA修复，导致DNA损伤积累，并显著诱导细胞凋亡、分化和生长停滞，并增加AML细胞对化疗药物的敏感性，而不影响正常细胞。此外，GADD 45 g在AML中通过组蛋白脱乙酰化而表观遗传学沉默，并且其表达在携带这些遗传异常的患者中通过癌基因FLT 3-ITD和MLL-AF 9进一步下调。组蛋白脱乙酰酶1/2抑制剂罗米地辛与FLT 3酪氨酸激酶抑制剂AC 220或布罗莫结构域抑制剂JQ 1联合使用，通过双重激活GADD 45 g，分别对FLT 3-ITD+和MLL-AF 9（+）AML发挥协同抗白血病作用。这些发现揭示了GADD 45 g的选择性抗白血病作用的迄今未报道的证据，并为治疗FLT 3-ITD+和MLL-AF 9（+）AML提供了新的策略。
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy for which there is an unmet need for novel treatment strategies. Here, we characterize the growth arrest and DNA damage-inducible gene gamma (GADD45g) as a novel tumor suppressor in AML. We show that GADD45g is preferentially silenced in AML, especially in AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations and mixed-lineage leukemia (MLL)-rearrangements, and reduced expression of GADD45g is correlated with poor prognosis in patients with AML. Upregulation of GADD45g impairs homologous recombination DNA repair, leading to DNA damage accumulation, and dramatically induces apoptosis, differentiation, and growth arrest and increases sensitivity of AML cells to chemotherapeutic drugs, without affecting normal cells. In addition, GADD45g is epigenetically silenced by histone deacetylation in AML, and its expression is further downregulated by oncogenes FLT3-ITD and MLL-AF9 in patients carrying these genetic abnormalities. Combination of the histone deacetylase 1/2 inhibitor romidepsin with the FLT3 tyrosine kinase inhibitor AC220 or the bromodomain inhibitor JQ1 exerts synergistic antileukemic effects on FLT3-ITD+ and MLL-AF9(+) AML, respectively, by dually activating GADD45g. These findings uncover hitherto unreported evidence for the selective antileukemic role of GADD45g and provide novel strategies for the treatment of FLT3-ITD+ and MLL-AF9(+) AML.