Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia

Lu, Junyan; Cannizzaro, Ester; Meier-Abt, Fabienne; Scheinost, Sebastian; Bruch, Peter‐Martin; Giles, Holly; Luetge, Almut; Hüllein, Jennifer; Wagner, Lena; Giacopelli, Brian; Nadeu, Ferran; Delgado, Julio; Campo, Elı́as; Mangolini, Maurizio; Ringshausen, Ingo; Böttcher, Martin; Mougiakakos, Dimitrios; Jacobs, Andrea; Bodenmiller, Bernd; Dietrich, Sascha; Oakes, Christopher C.; Zenz, Thorsten; Huber, Wolfgang

doi:10.1038/s43018-021-00216-6

Cited by 38 publications

(32 citation statements)

References 81 publications

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“…However, in other typical translocations in leukemia—for example, MLL-AF9—OXPHOS occurs preferentially. That is also the case of CLL, which does not follow the Warburg effect ( 101 ) ( Figure 2B ). In fact, the general trend of cancer cells is to over-induce glycolysis while mitochondria continue to function as in the non-pathological conditions ( 102 ), which shows that cells still use mitochondrial metabolism and can resort to its excessive use if needed.…”

Section: Metabolism In Leukemia: Not As Simple As Originally Thoughtmentioning

confidence: 72%

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

Romo-González

Ijurko²,

Hernández‐Hernández³

2022

Front. Immunol.

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Reactive oxygen species (ROS), previously considered toxic by-products of aerobic metabolism, are increasingly recognized as regulators of cellular signaling. Keeping ROS levels low is essential to safeguard the self-renewal capacity of hematopoietic stem cells (HSC). HSC reside in a hypoxic environment and have been shown to be highly dependent on the glycolytic pathway to meet their energy requirements. However, when the differentiation machinery is activated, there is an essential enhancement of ROS together with a metabolic shift toward oxidative metabolism. Initiating and sustaining leukemia depend on the activity of leukemic stem cells (LSC). LSC also show low ROS levels, but unlike HSC, LSC rely on oxygen to meet their metabolic energetic requirements through mitochondrial respiration. In contrast, leukemic blasts show high ROS levels and great metabolic plasticity, both of which seem to sustain their invasiveness. Oxidative stress and metabolism rewiring are recognized as hallmarks of cancer that are intimately intermingled. Here we present a detailed overview of these two features, sustained at different levels, that support a two-way relationship in leukemia. Modifying ROS levels and targeting metabolism are interesting therapeutic approaches. Therefore, we provide the most recent evidence on the modulation of oxidative stress and metabolism as a suitable anti-leukemic approach.

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Section: Metabolism In Leukemia: Not As Simple As Originally Thoughtmentioning

confidence: 72%

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

Romo-González

Ijurko²,

Hernández‐Hernández³

2022

Front. Immunol.

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“…CLL Proliferative Drive (CLL‐PD) is a recently discovered molecular biomarker profile that captures the proliferative capacity of CLL cells based on data from multiple omic layers (Lu et al , 2021 ). CLL‐PD was significantly higher in C3 samples than in C4 and higher in C2 samples than in C1 (Appendix Fig S5A ).…”

Section: Resultsmentioning

confidence: 99%

“…The question whether the distinct response ex vivo is caused by a higher intrinsic activity of these pathways in vivo remains open and would be an interesting topic of further research. Further, we link microenvironmental response phenotypes to the CLL Proliferative Drive (Lu et al , 2021 ), further characterising the biology of this newly proposed patient stratification method.…”

Section: Discussionmentioning

confidence: 99%

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Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

Bruch

Giles

Kolb

et al. 2022

Molecular Systems Biology

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The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll‐like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL‐infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell‐extrinsic mechanisms of drug resistance and disease progression.

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“…As similar ex vivo assays can be readily performed on cell lines and primary samples, with established platforms and ready to use datasets for both drug sensitivity profiling [13,[15][16][17] and drug-protein profiling [14], we expect our approach to be adaptable to different diseases.…”

Section: Introductionmentioning

confidence: 99%

Inferring tumor-specific cancer dependencies through integrating ex vivo drug response assays and drug-protein profiling

Batzilla

Kivioja

et al. 2022

PLoS Comput Biol

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The development of cancer therapies may be improved by the discovery of tumor-specific molecular dependencies. The requisite tools include genetic and chemical perturbations, each with its strengths and limitations. Chemical perturbations can be readily applied to primary cancer samples at large scale, but mechanistic understanding of hits and further pharmaceutical development is often complicated by the fact that a chemical compound has affinities to multiple proteins. To computationally infer specific molecular dependencies of individual cancers from their ex vivo drug sensitivity profiles, we developed a mathematical model that deconvolutes these data using measurements of protein-drug affinity profiles. Through integrating a drug-kinase profiling dataset and several drug response datasets, our method, DepInfeR, correctly identified known protein kinase dependencies, including the EGFR dependence of HER2+ breast cancer cell lines, the FLT3 dependence of acute myeloid leukemia (AML) with FLT3-ITD mutations and the differential dependencies on the B-cell receptor pathway in the two major subtypes of chronic lymphocytic leukemia (CLL). Furthermore, our method uncovered new subgroup-specific dependencies, including a previously unreported dependence of high-risk CLL on Checkpoint kinase 1 (CHEK1). The method also produced a detailed map of the kinase dependencies in a heterogeneous set of 117 CLL samples. The ability to deconvolute polypharmacological phenotypes into underlying causal molecular dependencies should increase the utility of high-throughput drug response assays for functional precision oncology.

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Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia

Cited by 38 publications

References 81 publications

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

Reactive Oxygen Species and Metabolism in Leukemia: A Dangerous Liaison

Drug‐microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

Inferring tumor-specific cancer dependencies through integrating ex vivo drug response assays and drug-protein profiling

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