Evidence map›Paper›PMID 37873284›Full record

ArticlebioRxiv : the preprint server for biology2023

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium.

Anagha Inguva Sheth, Krysta Engel, Hunter Tolison, Mark J Althoff, Maria L Amaya, Anna Krug, Tracy Young, Shanshan Pei, Sweta B Patel, Mohammad Minhajuddin and 14 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 6 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors at 3 institutions in 3 countries.

Anagha Inguva ShethDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Krysta EngelDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Hunter TolisonDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Mark J AlthoffDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Maria L AmayaDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Anna KrugDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Tracy YoungDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Shanshan PeiLiangzhu Laboratory, Zhejiang University Medical Center, Bone Marrow Transplantation Center, Hangzhou, China.
Sweta B PatelDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Mohammad MinhajuddinDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Amanda WintersDivision of Pediatric Hematology and Oncology, University of Colorado School of Medicine, Aurora, CO, USA.
Regan MillerDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Ian SheltonDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Jonathan St-GermainPrincess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Tianyi LingPrincess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Courtney JonesPrincess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Brian RaughtPrincess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Austin GillenDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Monica RansomDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Sarah StaggsDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Clayton A SmithDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Daniel A PollyeaDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Brett M StevensDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
Craig T JordanDivision of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
University of Colorado Denver · USUniversity Health Network · CAZhejiang University · CN

Funding

PILOT STUDY--SUBSTRATE METABOLISM IN EXTREMELY LOW BIRTH WEIGHT INFANTSP30DK048520 · NIDDK · UNIVERSITY OF COLORADO DENVER · PI Edward L Melanson · 1995 to 2026
$32.6M
Therapeutic Targeting of Human AML Stem CellsR35CA242376 · NCI · UNIVERSITY OF COLORADO DENVER · PI Craig T. Jordan · 2020 to 2026
$5.6M
Understanding the unique dependency for MCL1 in Ven/Aza resistant AMLF32CA275350 · NCI · UNIVERSITY OF COLORADO DENVER · PI ALTHOFF, MARK JORDAN · 2022 to 2024
$223k
The Role of BCL2 Mediated Calcium Signaling in Leukemia Stem Cell MetabolismF30CA254251 · NCI · UNIVERSITY OF COLORADO DENVER · PI INGUVA, ANAGHA · 2021 to 2023
$120k
BLRD VA I01 BX004768BLRD VA IK2 BX005603NCI NIH HHS F30 CA254251NCI NIH HHS F32 CA275350NCI NIH HHS R35 CA242376NIDDK NIH HHS P30 DK048520
6 · The paper itself

Abstract

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.

Identifiers

PMID37873284
PMCPMC10592899
OpenAlexW4387309944

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.