Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia
Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia
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DOI：
10.1182/blood-2014-03-563304
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发表时间：
2015-02-05
期刊：
影响因子：
20.3
通讯作者：
Ishikawa, Fumihiko
中科院分区：
文献类型：
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作者：
Aoki, Yuki;Watanabe, Takashi;Ishikawa, Fumihiko
混合系白血病（MLL）基因与AF 4、AF 9或ENL易位导致淋巴和髓系同时受累的急性白血病。我们采用异种移植模型对原发性婴儿ML重排白血病的白血病起始细胞（LIC）进行了鉴定。在MLL-AF 4患者中，CD 34（+）CD 38（+）CD 19（+）和CD 34（-）CD 19（+）细胞引发白血病，而在MLL-AF 9患者中，CD 34（-）CD 19（+）细胞是LIC。在MLL-ENL患者中，CD 34（+）或CD 34（-）细胞是LIC，这取决于CD 34表达模式。相反，在这些MLL易位的患者中，CD 34（+）CD 38（-）CD 19（-）CD 33（-）细胞富含具有体内长期多谱系造血再增殖能力的正常造血干细胞（HSC）。尽管LIC在体内产生具有克隆性免疫球蛋白重链（IGH）重排的白血病细胞，但CD 34（+）CD 38（-）CD 19（-）CD 33（-）细胞用B细胞重新填充受体骨髓和脾脏，显示广泛的多克隆IGH重排，并且受体胸腺具有CD 4（+）单阳性（SP）、CD 8（+）SP和CD 4（+）CD 8（+）双阳性（DP）T细胞。总体基因表达谱显示，与正常HSC相比，CD 9、CD 32和CD 24在MLL-AF 4、MLL-AF 9和MLL-ENL LIC中过度表达。在患者样本中，这些分子在CD 34（+）CD 38（+）和CD 34（-）LIC中表达，但在CD 34（+）CD 38（-）CD 19（-）CD 33（-）HSC中不表达。在原发性人类MLL重排的急性淋巴细胞白血病中鉴定LIC和LIC特异性分子可能导致MLL重排白血病的治疗策略的改进。
Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.