Stem Cell Program, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
Blood. 2012 Jan 12;119(2):494-502. doi: 10.1182/blood-2011-06-359232. Epub 2011 Nov 18.
The characterization and targeting of Philadelphia chromosome positive (Ph(+)) acute lymphoblastic leukemia (ALL)-initiating cells remains unresolved. Expression of the polycomb protein Bmi1 is up-regulated in patients with advanced stages of chronic myelogenous leukemia (CML). We report that Bmi1 transforms and reprograms CML B-lymphoid progenitors into stem cell leukemia (Scl) promoter-driven, self-renewing, leukemia-initiating cells to result in B-lymphoid leukemia (B-ALL) in vivo. In vitro, highly proliferating and serially replatable myeloid and lymphoid colony-forming cultures could be established from BCR-ABL and Bmi1 coexpressing progenitors. However, unlike in vivo expanded CML B-lymphoid progenitors, hematopoietic stem cells, or multipotent progenitors, coexpressing BCR-ABL and Bmi1 did not initiate or propagate leukemia in a limiting dilution assay. Inducible genetic attenuation of BCR-ABL reversed Bmi1-driven B-ALL development, which was accompanied by induction of apoptosis of leukemic B-lymphoid progenitors and by long-term animal survival, suggesting that BCR-ABL is required to maintain B-ALL and that BCR-ABL and Bmi1 cooperate toward blast transformation in vivo. Our data indicate that BCR-ABL targeting itself is required to eradicate Ph(+)/Bmi1(+) B-ALL-initiating cells and confirm their addiction to BCR-ABL signaling.
费城染色体阳性（Ph(+））急性淋巴细胞白血病（ALL）起始细胞的特征和靶向仍然未得到解决。多梳蛋白 Bmi1 的表达在慢性粒细胞白血病（CML）的晚期患者中上调。我们报告称，Bmi1 可将 CML B 淋巴细胞祖细胞转化并重新编程为干细胞白血病（Scl）启动子驱动的、自我更新的、起始细胞，从而导致体内 B 淋巴细胞白血病（B-ALL）。在体外，从共表达 BCR-ABL 和 Bmi1 的祖细胞中可以建立高度增殖和可连续复制的髓样和淋巴样集落形成培养物。然而，与体内扩增的 CML B 淋巴细胞祖细胞、造血干细胞或多能祖细胞不同，共表达 BCR-ABL 和 Bmi1 的细胞在有限稀释测定中不会起始或传播白血病。BCR-ABL 的可诱导遗传衰减逆转了 Bmi1 驱动的 B-ALL 发展，伴随着白血病 B 淋巴细胞祖细胞的凋亡诱导和长期动物存活，表明 BCR-ABL 是维持 B-ALL 所必需的，并且 BCR-ABL 和 Bmi1 在体内合作进行原始细胞转化。我们的数据表明，BCR-ABL 靶向本身是根除 Ph(+)/Bmi1(+) B-ALL 起始细胞所必需的，并证实它们依赖于 BCR-ABL 信号。
