Aoki Yuki, Watanabe Takashi, Saito Yoriko, Kuroki Yoko, Hijikata Atsushi, Takagi Masatoshi, Tomizawa Daisuke, Eguchi Mariko, Eguchi-Ishimae Minenori, Kaneko Akiko, Ono Rintaro, Sato Kaori, Suzuki Nahoko, Fujiki Saera, Koh Katsuyoshi, Ishii Eiichi, Shultz Leonard D, Ohara Osamu, Mizutani Shuki, Ishikawa Fumihiko
Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;
Blood. 2015 Feb 5;125(6):967-80. doi: 10.1182/blood-2014-03-563304. Epub 2014 Dec 23.
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.
混合谱系白血病（MLL）基因与AF4、AF9或ENL发生易位会导致急性白血病，同时累及淋巴系和髓系。我们使用异种移植模型对原发性婴儿MLL重排白血病中的白血病起始细胞（LIC）进行了特征分析。在MLL-AF4患者中，CD34(+)CD38(+)CD19(+)和CD34(-)CD19(+)细胞引发白血病，而在MLL-AF9患者中，CD34(-)CD19(+)细胞是LIC。在MLL-ENL患者中，根据CD34表达模式，CD34(+)或CD34(-)细胞均为LIC。相比之下，在这些MLL易位患者中，CD34(+)CD38(-)CD19(-)CD33(-)细胞富含具有体内长期多谱系造血重建能力的正常造血干细胞（HSC）。尽管LIC在体内产生了具有克隆性免疫球蛋白重链（IGH）重排的白血病细胞，但CD34(+)CD38(-)CD19(-)CD33(-)细胞能使受体骨髓和脾脏重新填充B细胞，表现出广泛的多克隆IGH重排，并使受体胸腺重新填充CD4(+)单阳性（SP）、CD8(+)SP和CD4(+)CD8(+)双阳性（DP）T细胞。全基因组表达谱分析显示，与正常HSC相比，CD9、CD32和CD24在MLL-AF4、MLL-AF9和MLL-ENL LIC中表达上调。在患者样本中，这些分子在CD34(+)CD38(+)和CD(-)34 LIC中表达，但在CD34(+)CD38(-)CD19(-)CD33(-)HSC中不表达。鉴定原发性人类MLL重排急性淋巴细胞白血病中的LIC和LIC特异性分子可能会改善MLL重排白血病的治疗策略。
