Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.
CP: Cancer
CP: Metabolism
leukemia
metabolism
stem cell
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 04 2022
26 04 2022
Historique:
received:
13
10
2021
revised:
24
01
2022
accepted:
07
04
2022
entrez:
27
4
2022
pubmed:
28
4
2022
medline:
30
4
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35476984
pii: S2211-1247(22)00516-2
doi: 10.1016/j.celrep.2022.110752
pmc: PMC9099058
mid: NIHMS1801896
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
110752Subventions
Organisme : NCI NIH HHS
ID : K08 CA222684
Pays : United States
Organisme : NIDDK NIH HHS
ID : K08 DK114527
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL134812
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002541
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests G.Q.D. holds equity in companies pursuing anti-cancer treatments (including Epizyme and 28-7 Therapeutics) and patents related to cancer therapeutics. A.K.S. reports compensation for consulting and/or science advisory board (SAB) membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics Limited, Empress Therapeutics, FL82, and Dahlia Biosciences.
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