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低氧、糖酵解代谢是 B 急性淋巴细胞白血病起始细胞的一个脆弱性。

Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.

机构信息

Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.

Stem Cell Transplantation Program, Department of Hematology, Boston Children's Hospital, Boston, MA 02115, USA.

出版信息

Cell Rep. 2022 Apr 26;39(4):110752. doi: 10.1016/j.celrep.2022.110752.

DOI:10.1016/j.celrep.2022.110752
PMID:35476984
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9099058/
Abstract

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.

摘要

高危形式的 B 急性淋巴细胞白血病 (B-ALL) 仍然是一个治疗挑战。白血病起始细胞 (LICs) 自我更新并引发复发，因此一直是深入研究的主题；然而，高危 B-ALL 中的 LIC 特性尚未得到很好的理解。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) 中的 LIC 频率相比，MLL-r B-ALL 中可移植的 LIC 很丰富。尽管我们发现多能性、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使原始细胞增殖受阻，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，为异种移植系统提供治疗益处。这些发现深入了解了 MLL-r B-ALL 的侵袭性，并为缺氧和糖酵解的治疗靶向提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/764f/9099058/853fccdcd09c/nihms-1801896-f0008.jpg
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