Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Hematology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
J Cell Mol Med. 2021 Mar;25(6):3124-3135. doi: 10.1111/jcmm.16377. Epub 2021 Feb 17.
Acute myeloid leukaemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukaemia (MLL) is an aggressive subtype with low overall survival. Bortezomib (Bort) is first applied in multiple myeloma. However, whether bort possesses anti-self-renewal and leukemogenesis of leukaemia stem cell (LSC) in AML with MLL rearrangements is still unclear. Here, we found that bort suppressed cell proliferation and decreased colony formation in human and murine leukaemic blasts. Besides, bort reduced the frequency and function of LSC, inhibited the progression, and extended the overall survival in MLL-AF9 (MF9) -transformed leukaemic mice. Furthermore, bort decreased the percentage of human LSC (CD34 CD38 ) cells and extended the overall survival in AML blasts-xenografted NOD/SCID-IL2Rγ (NSG) mice. Mechanistically, cyclin dependent kinase 6 (CDK6) was identified as a bort target by RNA sequencing. Bort reduced the expressions of CDK6 by inhibiting NF ĸB recruitment to the promoter of CDK6, leading to the abolishment of NF ĸB DNA-binding activity for CDK6 promoter. Overexpression of CDK6 partially rescued bort-induced anti-leukemogenesis. Most importantly, bort had little side-effect against the normal haematological stem and progenitor cell (HSPC) and did not affect CDK6 expression in normal HSPC. In conclusion, our results suggest that bort selectively targets LSC in MLL rearrangements. Bort might be a prospective drug for AML patients bearing MLL rearrangements.
急性髓系白血病(AML)伴涉及 H3K4 甲基转移酶混合谱系白血病(MLL)的染色体重排是一种侵袭性亚型,总体存活率低。硼替佐米(Bort)首先应用于多发性骨髓瘤。然而,Bort 是否具有抗自我更新和白血病干细胞(LSC)在 AML 伴 MLL 重排中的白血病发生作用尚不清楚。在这里,我们发现 Bort 抑制了人源和鼠源白血病母细胞的增殖和集落形成。此外,Bort 降低了 LSC 的频率和功能,抑制了 MLL-AF9(MF9)转化的白血病小鼠的进展,并延长了总生存期。此外,Bort 降低了人源 LSC(CD34 CD38)细胞的比例,并延长了 AML 母细胞异种移植 NOD/SCID-IL2Rγ(NSG)小鼠的总生存期。从机制上讲,通过 RNA 测序鉴定出周期蛋白依赖性激酶 6(CDK6)是 Bort 的靶标。Bort 通过抑制 NF ĸB 募集到 CDK6 启动子,降低 CDK6 的表达,从而消除 NF ĸB DNA 结合活性对 CDK6 启动子的作用。CDK6 的过表达部分挽救了 Bort 诱导的抗白血病发生作用。最重要的是,Bort 对正常造血干细胞和祖细胞(HSPC)几乎没有副作用,并且不会影响正常 HSPC 中 CDK6 的表达。总之,我们的结果表明 Bort 选择性地靶向 MLL 重排中的 LSC。Bort 可能是一种有前途的药物,适用于患有 MLL 重排的 AML 患者。