PMID- 32695673 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210406 IS - 2234-943X (Print) IS - 2234-943X (Electronic) IS - 2234-943X (Linking) VI - 10 DP - 2020 TI - Inhibition of Oxidative Phosphorylation Reverses Bone Marrow Hypoxia Visualized in Imageable Syngeneic B-ALL Mouse Model. PG - 991 LID - 10.3389/fonc.2020.00991 [doi] LID - 991 AB - Abnormally low level of interstitial oxygen, or hypoxia, is a hallmark of tumor microenvironment and a known promoter of cancer chemoresistance. Inside a solid tumor mass, the hypoxia stems largely from inadequate supply of oxygenated blood through sparse or misshapen tumor vasculature whilst oxygen utilization rates are low in typical tumor's glycolytic metabolism. In acute leukemias, however, markers of intracellular hypoxia such as increased pimonidazole adduct staining and HIF-1alpha stabilization are observed in advanced leukemic bone marrows (BM) despite an increase in BM vasculogenesis. We utilized intravital fast scanning two-photon phosphorescence lifetime imaging microscopy (FaST-PLIM) in a BCR-ABL B-ALL mouse model to image the extracellular oxygen concentrations (pO(2)) in leukemic BM, and we related the extracellular oxygen levels to intracellular hypoxia, vascular markers and local leukemia burden. We observed a transient increase in BM pO(2) in initial disease stages with intermediate leukemia BM burden, which correlated with an expansion of blood-carrying vascular network in the BM. Yet, we also observed increased formation of intracellular pimonidazole adducts in leukemic BM at the same time. This intermediate stage was followed by a significant decrease of extracellular pO(2) and further increase of intracellular hypoxia as leukemia cellularity overwhelmed BM in disease end-stage. Remarkably, treatment of leukemic mice with IACS-010759, a pharmacological inhibitor of mitochondrial Complex I, substantially increased pO(2) in the BM with advanced B-ALL, and it alleviated intracellular hypoxia reported by pimonidazole staining. High rates of oxygen consumption by B-ALL cells were confirmed by Seahorse assay including in ex vivo cells. Our results suggest that B-ALL expansion in BM is associated with intense oxidative phosphorylation (OxPhos) leading to the onset of metabolic BM hypoxia despite increased BM vascularization. Targeting mitochondrial respiration may be a novel approach to counteract BM hypoxia in B-ALL and, possibly, tumor hypoxia in other OxPhos-reliant malignancies. CI - Copyright (c) 2020 Rytelewski, Harutyunyan, Baran, Mallampati, Zal, Cavazos, Butler, Konoplev, El Khatib, Plunkett, Marszalek, Andreeff, Zal and Konopleva. FAU - Rytelewski, Mateusz AU - Rytelewski M AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Harutyunyan, Karine AU - Harutyunyan K AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Baran, Natalia AU - Baran N AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Mallampati, Saradhi AU - Mallampati S AD - Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Zal, M Anna AU - Zal MA AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Cavazos, Antonio AU - Cavazos A AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Butler, Jason M AU - Butler JM AD - Weill Cornell Medicine, Medical School of Biological Sciences, Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, United States. FAU - Konoplev, Sergej AU - Konoplev S AD - Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - El Khatib, Mirna AU - El Khatib M AD - Department of Biochemistry and Biophysics, The University of Pennsylvania, Philadelphia, PA, United States. FAU - Plunkett, Shane AU - Plunkett S AD - Department of Biochemistry and Biophysics, The University of Pennsylvania, Philadelphia, PA, United States. FAU - Marszalek, Joseph R AU - Marszalek JR AD - TRACTION, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Andreeff, Michael AU - Andreeff M AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Zal, Tomasz AU - Zal T AD - Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Konopleva, Marina AU - Konopleva M AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 EB018464/EB/NIBIB NIH HHS/United States GR - R01 CA231364/CA/NCI NIH HHS/United States GR - R24 NS092986/NS/NINDS NIH HHS/United States GR - K25 HL145092/HL/NHLBI NIH HHS/United States GR - R01 CA155056/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20200630 PL - Switzerland TA - Front Oncol JT - Frontiers in oncology JID - 101568867 PMC - PMC7339962 OTO - NOTNLM OT - acute lymphobastic leukemia OT - bone marrow OT - hypoxia OT - leukemia OT - oxidative phosphorylation OT - oxygen OT - vascularity EDAT- 2020/07/23 06:00 MHDA- 2020/07/23 06:01 PMCR- 2020/01/01 CRDT- 2020/07/23 06:00 PHST- 2020/02/26 00:00 [received] PHST- 2020/05/19 00:00 [accepted] PHST- 2020/07/23 06:00 [entrez] PHST- 2020/07/23 06:00 [pubmed] PHST- 2020/07/23 06:01 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fonc.2020.00991 [doi] PST - epublish SO - Front Oncol. 2020 Jun 30;10:991. doi: 10.3389/fonc.2020.00991. eCollection 2020.