Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-?B-dependent inhibition of cyclin dependent kinase 6 in MLL-rearranged myeloid leukemia

Acute myeloid leukemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) is an aggressive subtype with low overall survival. MLL rearrangements rapidly transform hematological stem and progenitor cell (HSPC) to leukemia stem cell (LSC). Bortezomib (Velcade) is used widely in hematological malignancies. However, it is still unknown whether bortezomib possesses anti-self-renewal and anti-leukemogenesis of LSC in AML with MLL rearrangements. Here, we found that bortezomib inhibited cell proliferation, induced apoptosis, and decreased colony formation in leukemic cell lines, primary AML blasts, and MLL-AF9-transformed murine leukemic blasts. Besides, bortezomib reduced the frequency and function of LSC, inhibited the progression, and prolonged Overall design: Examination of bortezomib-treated leukemia stem cells.

携带涉及组蛋白H3K4甲基转移酶混合谱系白血病（mixed-lineage leukemia, MLL）基因染色体重排的急性髓系白血病（acute myeloid leukemia, AML）是一类侵袭性亚型，总生存率偏低。MLL基因重排可快速将造血干祖细胞（hematological stem and progenitor cell, HSPC）转化为白血病干细胞（leukemia stem cell, LSC）。硼替佐米（bortezomib，商品名Velcade）已广泛应用于血液系统恶性肿瘤的治疗。然而，目前仍不明确硼替佐米是否对MLL重排型AML中的白血病干细胞具有抗自我更新及抗白血病生成的作用。本研究发现，硼替佐米可抑制白血病细胞系、原代AML原始细胞以及MLL-AF9转化的小鼠白血病原始细胞的增殖，诱导其凋亡，并降低其集落形成能力。此外，硼替佐米可降低白血病干细胞的频率与功能，抑制疾病进展并延长。整体实验设计：对经硼替佐米处理的白血病干细胞进行检测。