PMID- 34507353
OWN - NLM
STAT- MEDLINE
DCOM- 20211101
LR  - 20220401
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 5
IP  - 20
DP  - 2021 Oct 26
TI  - Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate 
      AML resistance to OxPhos inhibition.
PG  - 4233-4255
LID - 10.1182/bloodadvances.2020003661 [doi]
AB  - Acute myeloid leukemia (AML) cells are highly dependent on oxidative 
      phosphorylation (OxPhos) for survival, and they continually adapt to fluctuations 
      in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We 
      investigated how the BM microenvironment affects the response to OxPhos 
      inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. 
      Cellular adhesion, growth, and apoptosis assays, along with measurements of 
      expression of mitochondrial DNA and generation of mitochondrial reactive oxygen 
      species indicated that direct interactions with BM stromal cells triggered 
      compensatory activation of mitochondrial respiration and resistance to OxPhos 
      inhibition in AML cells. Mechanistically, inhibition of OxPhos induced transfer 
      of mitochondria derived from mesenchymal stem cells (MSCs) to AML cells via 
      tunneling nanotubes under direct-contact coculture conditions. Inhibition of 
      OxPhos also induced mitochondrial fission and increased functional mitochondria 
      and mitophagy in AML cells. Mitochondrial fission is known to enhance cell 
      migration, so we used electron microscopy to observe mitochondrial transport to 
      the leading edge of protrusions of AML cells migrating toward MSCs. We further 
      demonstrated that cytarabine, a commonly used antileukemia agent, increased 
      mitochondrial transfer of MSCs to AML cells triggered by OxPhos inhibition. Our 
      findings indicate an important role of exogenous mitochondrial trafficking from 
      BM stromal cells to AML cells as well as endogenous mitochondrial fission and 
      mitophagy in the compensatory adaptation of leukemia cells to energetic stress in 
      the BM microenvironment.
CI  - (c) 2021 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Saito, Kaori
AU  - Saito K
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
FAU - Zhang, Qi
AU  - Zhang Q
AD  - Section of Leukemia Biology Research, Department of Leukemia, The University of 
      Texas MD Anderson Cancer Center, Houston, TX.
FAU - Yang, Haeun
AU  - Yang H
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
FAU - Yamatani, Kotoko
AU  - Yamatani K
AUID- ORCID: 0000-0002-0162-1162
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
AD  - Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan.
FAU - Ai, Tomohiko
AU  - Ai T
AUID- ORCID: 0000-0003-0376-0227
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
FAU - Ruvolo, Vivian
AU  - Ruvolo V
AUID- ORCID: 0000-0003-4363-7258
AD  - Section of Molecular Hematology and Therapy, Department of Leukemia, The 
      University of Texas MD Anderson Cancer Center, Houston, TX.
FAU - Baran, Natalia
AU  - Baran N
AUID- ORCID: 0000-0003-0618-4798
AD  - Section of Leukemia Biology Research, Department of Leukemia, The University of 
      Texas MD Anderson Cancer Center, Houston, TX.
FAU - Cai, Tianyu
AU  - Cai T
AD  - Section of Leukemia Biology Research, Department of Leukemia, The University of 
      Texas MD Anderson Cancer Center, Houston, TX.
FAU - Ma, Helen
AU  - Ma H
AD  - Section of Leukemia Biology Research, Department of Leukemia, The University of 
      Texas MD Anderson Cancer Center, Houston, TX.
FAU - Jacamo, Rodrigo
AU  - Jacamo R
AD  - Section of Molecular Hematology and Therapy, Department of Leukemia, The 
      University of Texas MD Anderson Cancer Center, Houston, TX.
FAU - Kuruvilla, Vinitha
AU  - Kuruvilla V
AD  - Section of Leukemia Biology Research, Department of Leukemia, The University of 
      Texas MD Anderson Cancer Center, Houston, TX.
FAU - Imoto, Junichi
AU  - Imoto J
AD  - Center for Information Biology, National Institute of Genetics, Shizuoka, Japan.
FAU - Kinjo, Sonoko
AU  - Kinjo S
AD  - Center for Information Biology, National Institute of Genetics, Shizuoka, Japan.
FAU - Ikeo, Kazuho
AU  - Ikeo K
AD  - Center for Information Biology, National Institute of Genetics, Shizuoka, Japan.
FAU - Moriya, Kaori
AU  - Moriya K
AD  - Laboratory of Morphology and Image Analysis, and.
FAU - Suzuki, Koya
AU  - Suzuki K
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
AD  - Research Institute for Diseases of Old Age, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
FAU - Miida, Takashi
AU  - Miida T
AUID- ORCID: 0000-0002-4294-8030
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
FAU - Kim, Yong-Mi
AU  - Kim YM
AUID- ORCID: 0000-0003-3793-6438
AD  - Pediatrics and Pathology, Keck School of Medicine, University of Southern 
      California, Los Angeles, CA.
FAU - Vellano, Christopher P
AU  - Vellano CP
AD  - TRACTION, Therapeutics Discovery Division, The University of Texas MD Anderson 
      Cancer Center, Houston, TX; and.
FAU - Andreeff, Michael
AU  - Andreeff M
AUID- ORCID: 0000-0002-1144-1958
AD  - Section of Molecular Hematology and Therapy, Department of Leukemia, The 
      University of Texas MD Anderson Cancer Center, Houston, TX.
FAU - Marszalek, Joseph R
AU  - Marszalek JR
AD  - TRACTION, Therapeutics Discovery Division, The University of Texas MD Anderson 
      Cancer Center, Houston, TX; and.
FAU - Tabe, Yoko
AU  - Tabe Y
AUID- ORCID: 0000-0002-3734-0346
AD  - Department of Clinical Laboratory Medicine, Juntendo University Graduate School 
      of Medicine, Tokyo, Japan.
AD  - Section of Molecular Hematology and Therapy, Department of Leukemia, The 
      University of Texas MD Anderson Cancer Center, Houston, TX.
AD  - Department of Next Generation Hematology Laboratory Medicine, Juntendo University 
      Graduate School of Medicine, Tokyo, Japan.
FAU - Konopleva, Marina
AU  - Konopleva M
AUID- ORCID: 0000-0002-9347-2212
AD  - Section of Leukemia Biology Research, Department of Leukemia, The University of 
      Texas MD Anderson Cancer Center, Houston, TX.
LA  - eng
GR  - P50 CA100632/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (IACS-010759)
RN  - 0 (Oxadiazoles)
RN  - 0 (Piperidines)
SB  - IM
MH  - Humans
MH  - *Leukemia, Myeloid, Acute/drug therapy/metabolism
MH  - Mitochondria/metabolism
MH  - Mitochondrial Dynamics
MH  - Oxadiazoles
MH  - *Oxidative Phosphorylation
MH  - Piperidines
MH  - Tumor Microenvironment
PMC - PMC8945617
EDAT- 2021/09/11 06:00
MHDA- 2021/11/03 06:00
PMCR- 2021/10/25
CRDT- 2021/09/10 20:33
PHST- 2020/10/22 00:00 [received]
PHST- 2021/06/09 00:00 [accepted]
PHST- 2021/09/11 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2021/09/10 20:33 [entrez]
PHST- 2021/10/25 00:00 [pmc-release]
AID - S2473-9529(21)00537-1 [pii]
AID - 2021/ADV2020003661 [pii]
AID - 10.1182/bloodadvances.2020003661 [doi]
PST - ppublish
SO  - Blood Adv. 2021 Oct 26;5(20):4233-4255. doi: 10.1182/bloodadvances.2020003661.