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1.
Nature ; 630(8017): 728-735, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38778101

ABSTRACT

Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells1. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell malignancies2. However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs2-5. Here we demonstrate that an antibody-drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specific depletion of the entire haematopoietic system, including HSCs. Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system, irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies.


Subject(s)
Hematologic Neoplasms , Hematopoiesis , Immunoconjugates , Leukocyte Common Antigens , Animals , Female , Humans , Male , Mice , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/therapy , Hematologic Neoplasms/immunology , Hematopoiesis/drug effects , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Leukocyte Common Antigens/immunology , Leukocyte Common Antigens/metabolism , Cell Line, Tumor , Antibody Specificity
3.
J Exp Med ; 220(12)2023 12 04.
Article in English | MEDLINE | ID: mdl-37773046

ABSTRACT

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).


Subject(s)
Interleukin-3 Receptor alpha Subunit , Leukemia, Myeloid, Acute , Humans , Interleukin-3 Receptor alpha Subunit/metabolism , Epitopes , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Immunotherapy , Hematopoietic Stem Cells/metabolism , Immunotherapy, Adoptive
4.
Cancer Res ; 83(17): 2824-2838, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37327406

ABSTRACT

Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients. SIGNIFICANCE: CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.


Subject(s)
Leukemia, Myeloid, Acute , Humans , Animals , Mice , Leukemia, Myeloid, Acute/pathology , Treatment Outcome , Prognosis , Recurrence , Blast Crisis/pathology , Chronic Disease
5.
Leukemia ; 37(4): 765-775, 2023 04.
Article in English | MEDLINE | ID: mdl-36739349

ABSTRACT

Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.


Subject(s)
Leukemia, Myeloid, Acute , Mitochondrial Dynamics , Humans , Mitochondrial Dynamics/genetics , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Energy Metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Mitochondrial Proteins/metabolism
6.
Cell Rep ; 38(1): 110197, 2022 01 04.
Article in English | MEDLINE | ID: mdl-34986346

ABSTRACT

AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Imidazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Pyrimidinones/pharmacology , Sulfonamides/pharmacology , Unfolded Protein Response/physiology , eIF-2 Kinase/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Antineoplastic Agents/pharmacology , Apoptosis/physiology , Cell Line, Tumor , Citric Acid Cycle/drug effects , Drug Evaluation, Preclinical , Female , HEK293 Cells , HL-60 Cells , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Male , Mice , Middle Aged , Mitochondria/metabolism , Oxidative Phosphorylation/drug effects , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , THP-1 Cells , U937 Cells , Young Adult
7.
Haematologica ; 107(2): 403-416, 2022 02 01.
Article in English | MEDLINE | ID: mdl-33406814

ABSTRACT

APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.


Subject(s)
Ferroptosis , Leukemia, Myeloid, Acute , Cell Death , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Quinuclidines/therapeutic use
8.
Cancer Discov ; 12(2): 432-449, 2022 02.
Article in English | MEDLINE | ID: mdl-34531254

ABSTRACT

CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancer, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro using established cell lines, evaluating the physiologic relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to validate and prioritize AML-enriched dependencies in vivo, including in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, further highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets. SIGNIFICANCE: There is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, both of which represent novel therapeutic opportunities.This article is highlighted in the In This Issue feature, p. 275.


Subject(s)
Antineoplastic Agents/therapeutic use , CRISPR-Cas Systems , Leukemia, Myeloid, Acute/drug therapy , Precision Medicine , Xenograft Model Antitumor Assays , Animals , Humans , Leukemia, Myeloid, Acute/genetics
9.
Cancers (Basel) ; 13(23)2021 Nov 27.
Article in English | MEDLINE | ID: mdl-34885077

ABSTRACT

The treatment of acute myeloid leukemia (AML) remains a challenge especially among the elderly. The Bcl-2 inhibitor venetoclax recently showed significant survival benefits in AML patients when combined to low-dose cytarabine or azacitidine. Bcl-2 inhibition initiate mitochondrial apoptosis, but also respiration and cellular ATP production in AML. AMP-Activated Protein Kinase (AMPK) is a central energy sensor activated by increased AMP:ATP ratio to restore the cellular energy balance. Unexpectedly, we observed that venetoclax inhibited AMPK activity through caspase-dependent degradation of AMPK subunits in AML cells. On the other hand, genetic models of AMPK invalidation and re-expression suggested that AMPK participated to the early stages of apoptotic response through a negative regulation of multi-domain anti-apoptotic effectors such as Mcl-1 or Bcl-xL. Together our results suggested a new link between AMPK and Bcl-2-dependent mitochondrial apoptosis that participated to the anti-leukemic activity of venetoclax in AML.

10.
J Exp Med ; 218(5)2021 05 03.
Article in English | MEDLINE | ID: mdl-33760042

ABSTRACT

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid ß-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.


Subject(s)
Drug Resistance, Neoplasm/genetics , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid/genetics , Mitochondria/genetics , Mutation , Acute Disease , Aminopyridines/pharmacology , Animals , Cell Line, Tumor , Doxycycline/pharmacology , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/pharmacology , Epigenesis, Genetic/drug effects , Glycine/analogs & derivatives , Glycine/pharmacology , HL-60 Cells , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Isocitrate Dehydrogenase/metabolism , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Isoenzymes/metabolism , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/metabolism , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Mitochondria/drug effects , Mitochondria/metabolism , Oxadiazoles/pharmacology , Oxidative Phosphorylation/drug effects , Piperidines/pharmacology , Pyridines/pharmacology , Triazines/pharmacology , Xenograft Model Antitumor Assays/methods
11.
Nat Commun ; 12(1): 422, 2021 01 18.
Article in English | MEDLINE | ID: mdl-33462236

ABSTRACT

Drug tolerant/resistant leukemic stem cell (LSC) subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these relapse-initiating cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncover that calcitonin receptor-like receptor (CALCRL) is expressed in RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM), and not CGRP, correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency, and sensitizes to cytarabine in patient-derived xenograft models. Mechanistically, the ADM-CALCRL axis drives cell cycle, DNA repair, and mitochondrial OxPHOS function of AML blasts dependent on E2F1 and BCL2. Finally, CALCRL depletion reduces LSC frequency of RICs post-chemotherapy in vivo. In summary, our data highlight a critical role of ADM-CALCRL in post-chemotherapy persistence of these cells, and disclose a promising therapeutic target to prevent relapse in AML.


Subject(s)
Adrenomedullin/metabolism , Antineoplastic Agents/pharmacology , Calcitonin Receptor-Like Protein/metabolism , Drug Resistance, Neoplasm/genetics , Leukemia, Myeloid, Acute/drug therapy , Neoplasm Recurrence, Local/genetics , Animals , Antineoplastic Agents/therapeutic use , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Receptor-Like Protein/genetics , Cell Cycle/drug effects , Cell Cycle/genetics , Cell Line, Tumor , DNA Repair/drug effects , DNA Repair/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Mice , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/prevention & control , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Oxidative Phosphorylation/drug effects , Primary Cell Culture , Prognosis , Xenograft Model Antitumor Assays
12.
FEBS Open Bio ; 11(1): 48-60, 2021 01.
Article in English | MEDLINE | ID: mdl-33410599

ABSTRACT

Acute myeloid leukaemia (AML) is a clonal disorder that affects hematopoietic stem cells or myeloid progenitors. One of the most common mutations that results in AML occurs in the gene encoding fms-like tyrosine kinase 3 (FLT3). Previous studies have demonstrated that AML cells expressing FLT3-internal tandem duplication (ITD) are more sensitive to the proteasome inhibitor bortezomib (Bz) than FLT3 wild-type cells, with this cytotoxicity being mediated by autophagy (Atg). Here, we show that proteasome inhibition with Bz results in modest but consistent proteaphagy in MOLM-14 leukemic cells expressing the FLT3-ITD mutation, but not in OCI-AML3 leukemic cells with wild-type FLT3. Chemical inhibition of Atg with bafilomycin A simultaneously blocked proteaphagy and resulted in the accumulation of the p62 Atg receptor in Bz-treated MOLM-14 cells. The use of ubiquitin traps revealed that ubiquitin plays an important role in proteasome-Atg cross-talk. The p62 inhibitor verteporfin blocked proteaphagy and, importantly, resulted in accumulation of high molecular weight forms of p62 and FLT3-ITD in Bz-treated MOLM-14 cells. Both Atg inhibitors enhanced Bz-induced apoptosis in FLT3-ITD-driven leukemic cells, highlighting the therapeutic potential of these treatments.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Bortezomib/pharmacology , Bortezomib/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Macroautophagy/drug effects , Macrolides/pharmacology , Macrolides/therapeutic use , Mutation , Proteasome Inhibitors/therapeutic use , Verteporfin/pharmacology , Verteporfin/therapeutic use
13.
Nat Cancer ; 2(11): 1204-1223, 2021 11.
Article in English | MEDLINE | ID: mdl-35122057

ABSTRACT

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.


Subject(s)
Cytarabine , Leukemia, Myeloid, Acute , Azacitidine/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cytarabine/pharmacology , Humans , Leukemia, Myeloid, Acute/drug therapy , Sulfonamides
14.
Nat Commun ; 11(1): 4056, 2020 08 13.
Article in English | MEDLINE | ID: mdl-32792483

ABSTRACT

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid ß-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.


Subject(s)
Autophagy/physiology , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/metabolism , Leukemia, Myeloid, Acute/metabolism , Leukemia/metabolism , Mitochondria/metabolism , Animals , Autophagy/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Proliferation/physiology , Flow Cytometry , Humans , Leukemia/genetics , Leukemia, Myeloid, Acute/pathology , Lipid Metabolism/genetics , Lipid Metabolism/physiology , Lipogenesis/genetics , Lipogenesis/physiology , Mice , Mitochondria/genetics , Oxidation-Reduction , Oxidative Phosphorylation
15.
Cancer Discov ; 10(10): 1544-1565, 2020 10.
Article in English | MEDLINE | ID: mdl-32641297

ABSTRACT

Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell-surface expression and activity is increased in patients with AML upon chemotherapy compared with diagnosis, and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes cytarabine resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive mitochondrial stress response. Finally, genetic and pharmacologic inhibition of CD39 ecto-ATPase activity blocks the mitochondrial reprogramming triggered by cytarabine treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML. SIGNIFICANCE: Extracellular ATP and CD39-P2RY13-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML.This article is highlighted in the In This Issue feature, p. 1426.


Subject(s)
Antigens, CD/metabolism , Apyrase/metabolism , Cytarabine/therapeutic use , Drug Resistance, Neoplasm/drug effects , Leukemia, Myeloid, Acute/drug therapy , Mitochondria/metabolism , Cytarabine/pharmacology , Female , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged
16.
Cancers (Basel) ; 12(7)2020 Jun 29.
Article in English | MEDLINE | ID: mdl-32610562

ABSTRACT

Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRß, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticancer drug acting through a different molecular mechanism, and conducted in vitro and in vivo combination tests on AML cell lines and patient primary tumors. We report here results from tests combining DDA with antimetabolite cytarabine (Ara-C), one of the main drugs used for AML treatment worldwide. We demonstrated that DDA potentiated and sensitized AML cells, including primary patient samples, to Ara-C in vitro and in vivo. Mechanistic studies revealed that this sensitization was LXRß-dependent and was due to the activation of lethal autophagy. This study demonstrates a positive in vitro and in vivo interaction between DDA and Ara-C, and supports the clinical evaluation of DDA in combination with Ara-C for the treatment of AML.

17.
Cancer Res ; 79(20): 5191-5203, 2019 Oct 15.
Article in English | MEDLINE | ID: mdl-31358527

ABSTRACT

Chemotherapies alter cellular redox balance and reactive oxygen species (ROS) content. Recent studies have reported that chemoresistant cells have an increased oxidative state in hematologic malignancies. In this study, we demonstrated that chemoresistant acute myeloid leukemia (AML) cells had a lower level of mitochondrial and cytosolic ROS in response to cytarabine (AraC) and overexpressed myeloperoxidase (MPO), a heme protein that converts hydrogen peroxide to hypochlorous acid (HOCl), compared with sensitive AML cells. High MPO-expressing AML cells were less sensitive to AraC in vitro and in vivo. They also produced higher levels of HOCl and exhibited an increased rate of mitochondrial oxygen consumption when compared with low MPO-expressing AML cells. Targeting MPO expression or enzyme activity sensitized AML cells to AraC treatment by triggering oxidative damage and sustaining oxidative stress, particularly in high MPO-expressing AML cells. This sensitization stemmed from mitochondrial superoxide accumulation, which impaired oxidative phosphorylation and cellular energetic balance, driving apoptotic death and selective eradication of chemoresistant AML cells in vitro and in vivo. Altogether, this study uncovers a noncanonical function of MPO enzyme in maintaining redox balance and mitochondrial energetic metabolism, therefore affecting downstream pathways involved in AML chemoresistance. SIGNIFICANCE: These findings demonstrate the role of myeloperoxidase in the regulation of ROS levels and sensitivity of AML cells to cytarabine, an essential chemotherapeutic backbone in the therapy of AML.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Cytarabine/pharmacology , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute/enzymology , Molecular Targeted Therapy , Neoplasm Proteins/antagonists & inhibitors , Peroxidase/antagonists & inhibitors , Animals , Apoptosis , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Gene Expression Profiling , Humans , Hypochlorous Acid/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Membrane Potential, Mitochondrial , Mice , Mice, Inbred NOD , Mice, SCID , Mitochondria/metabolism , Neoplasm Proteins/physiology , Oxidation-Reduction , Oxidative Stress , Peroxidase/physiology , RNA, Neoplasm/biosynthesis , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , Reactive Oxygen Species , Transcriptome , Xenograft Model Antitumor Assays
18.
Oncogenesis ; 8(8): 39, 2019 Jul 16.
Article in English | MEDLINE | ID: mdl-31311917

ABSTRACT

Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the KITD816V mutation in AML cells and contributed to support their cell proliferation and survival. Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KITD816V TF-1 cells. Downstream of KITD816V, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. Accordingly, STAT3 pharmacological inhibition or downregulation inhibited autophagy and reduced tumor growth both in vitro and in vivo. Taken together, our results support the notion that targeting autophagy or STAT3 opens up an exploratory pathway for finding new therapeutic opportunities for patients with CBF-AML or others malignancies with KITD816V mutations.

19.
Eur J Haematol ; 102(2): 131-142, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30325535

ABSTRACT

OBJECTIVES: We previously reported the prognostic value of serum ferritin in younger patients with intermediate-risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients. PATIENTS/MATERIALS/METHODS: Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML. RESULTS: We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf-KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine-resistant AML cells in a patient-derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone. CONCLUSION: Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.


Subject(s)
Apoferritins/genetics , Ferritins/blood , Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/genetics , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoferritins/blood , Biomarkers , Combined Modality Therapy , Drug Resistance, Neoplasm , Female , Ferritins/genetics , Gene Expression Profiling , Humans , Inflammation Mediators , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Odds Ratio , Oxidoreductases , Prognosis , Proportional Hazards Models , Treatment Outcome
20.
Haematologica ; 103(6): 988-998, 2018 06.
Article in English | MEDLINE | ID: mdl-29519869

ABSTRACT

Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; P<0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; P=0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in NPM1-mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with NPM1 mutation.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Dexamethasone/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Leukocytosis/drug therapy , Leukocytosis/pathology , Adolescent , Adult , Aged , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Leukemic/drug effects , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Leukocytosis/genetics , Male , Middle Aged , Mutation , Nuclear Proteins/genetics , Nucleophosmin , Prognosis , Recurrence , Remission Induction , Treatment Outcome , Young Adult
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