Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.
Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.
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DOI：
10.1016/j.celrep.2022.110752
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发表时间：
2022-04-26
期刊：
影响因子：
8.8
通讯作者：
Rowe, R. Grant
中科院分区：
文献类型：
--
作者：
Morris, Vivian;Wang, Dahai;Li, Zhiheng;Marion, William;Hughes, Travis;Sousa, Patricia;Harada, Taku;Sui, Shannan Ho;Naumenko, Sergey;Kalfon, Jeremie;Sensharma, Prerana;Falchetti, Marcelo;da Silva, Renan Vinicius;Candelli, Tito;Schneider, Pauline;Margaritis, Thanasis;Holstege, Frank C. P.;Pikman, Yana;Harris, Marian;Stam, Ronald W.;Orkin, Stuart H.;Koehler, Angela N.;Shalek, Alex K.;North, Trista E.;Pimkin, Maxim;Daley, George Q.;da Rocha, Edroaldo Lummertz;Rowe, R. Grant
高危 B 型急性淋巴细胞白血病 (B-ALL) 仍然是治疗挑战。白血病起始细胞（LIC）能够自我更新并引发复发，因此一直是深入研究的主题；然而，LICs 在高风险 B-ALL 中的特性尚不清楚。在这里，我们使用单细胞转录组学和定量异种移植来了解 MLL 重排 (MLL-r) B-ALL 中的 LIC。与报道的急性髓系白血病 (AML) 中 LIC 频率相比，MLL-r B-ALL 中的可移植 LIC 丰富。尽管我们发现多能、自我更新的 LIC 在表型未分化的 B-ALL 细胞中富集，但具有补充白血病细胞多样性能力的 LIC 可以从更成熟的细胞中出现。虽然抑制氧化磷酸化会削弱母细胞增殖，但这种干预会促进 LIC 的出现。相反，抑制缺氧和糖酵解会损害 MLL-r B-ALL LIC，从而在异种移植系统中提供治疗益处。这些发现深入了解了 MLL-r B-ALL 的侵袭性，并为针对缺氧和糖酵解的治疗靶向提供了理论依据。莫里斯等人。使用单细胞转录组学来鉴定 B 急性淋巴细胞白血病 (B-ALL) 中的候选起始细胞，其中 KMT2A/MLL1 基因座 (MLL-r) 发生重排，发现该细胞群是可塑的，并且处于可药理学靶向的缺氧状态。
High-risk forms of B-acute lymphoblastic leukemia (B-ALL) remain a therapeutic challenge. Leukemia-initiating cells (LICs) self-renew and spark relapse and therefore have been the subject of intensive investigation; however, the properties of LICs in high-risk B-ALL are not well understood. Here, we use single-cell transcriptomics and quantitative xenotransplantation to understand LICs in MLL-rearranged (MLL-r) B-ALL. Compared with reported LIC frequencies in acute myeloid leukemia (AML), engraftable LICs in MLL-r B-ALL are abundant. Although we find that multipotent, self-renewing LICs are enriched among phenotypically undifferentiated B-ALL cells, LICs with the capacity to replenish the leukemic cellular diversity can emerge from more mature fractions. While inhibiting oxidative phosphorylation blunts blast proliferation, this intervention promotes LIC emergence. Conversely, inhibiting hypoxia and glycolysis impairs MLL-r B-ALL LICs, providing a therapeutic benefit in xenotransplantation systems. These findings provide insight into the aggressive nature of MLL-r B-ALL and provide a rationale for therapeutic targeting of hypoxia and glycolysis. Morris et al. use single-cell transcriptomics to identify a candidate-initiating cell in B-acute lymphoblastic leukemia (B-ALL) with rearrangement of the KMT2A/MLL1 locus (MLL-r), finding that this population is plastic and exists in a hypoxic state that can be pharmacologically targeted.
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