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

Vivian Morris, Dahai Wang, Zhiheng Li, William Marion, Travis Hughes, Patricia Sousa, Taku Harada, Shannan Ho Sui, Sergey Naumenko, Jérémie Kalfon, Prerana Sensharma, Marcelo Falchetti, Renan Vinicius da Silva, Tito Candelli, Pauline Schneider, Thanasis Margaritis, Frank C.P. Holstege, Yana Pikman, Marian Harris, Ronald W. StamStuart H. Orkin, Angela N. Koehler, Alex K. Shalek, Trista E. North, Maxim Pimkin, George Q. Daley, Edroaldo Lummertz da Rocha, R. Grant Rowe

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Samenvatting

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.

Originele taal-2Engels
Artikelnummer110752
TijdschriftCell Reports
Volume39
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 26 apr. 2022

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