Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis

Yamashita, Masayuki; Dellorusso, Paul; Olson, Oakley C.; Passegué, Emmanuelle

doi:10.1038/s41568-020-0260-3

Cited by 120 publications

(150 citation statements)

References 198 publications

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“…In the era of next-generation sequencing, considerable progress has been made in understanding leukemogenesis, the genetic diversity of AML, gene-gene interactions, clonal evolution, and the assessment of treatment responses ( 5 – 11 ). Several functional categories of recurrent gene mutations that affect transcription factors, cell signalization, nucleophosmin, epigenetics, DNA methylation, and RNA splicing or the cohesin complex interact to produce the main hallmarks of cancer and transform hematopoietic progenitors into AML cells.…”

Section: Introductionmentioning

confidence: 99%

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Récher

2021

Front. Oncol.

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Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

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Section: Introductionmentioning

confidence: 99%

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Récher

2021

Front. Oncol.

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“…Homeostasis of healthy HSCs is regulated by oxidative phosphorylation (OXPHOS)-driven regeneration and glycolysis-mediated quiescence [ 65 ]. This balance is dysregulated in AML LSCs, as LSCs preferentially depend on mitochondrial OXPHOS to a greater degree than on glycolysis [ 7 ]. Considering that ATO activates quiescent HSCs and LSCs [ 66 ], the simultaneous inhibition of increased mitochondrial OXPHOS by venetoclax and unleashing LSC quiescence by ATO could have cooperatively sensitised LSCs to the combination treatment while sparing healthy HSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Although a substantial proportion of AML patients achieve a complete remission with intensive cytotoxic chemotherapy, most patients succumb to disease relapse [ 1 – 5 ]. AML relapse is considered to originate from leukaemia stem cells (LSCs), which are metabolically quiescent, capable of self-renewal, and responsible for chemotherapy resistance [ 6 , 7 ]. Therefore, more effective therapeutic strategies targeting LSCs are required to improve the cure rate in AML.…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukaemia cells

et al. 2021

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Background The evasion of apoptosis through dysregulated Bcl-2 family members is a hallmark of leukaemia stem cells (LSCs) in acute myeloid leukaemia (AML). Therefore, targeting Bcl-2 with venetoclax has been suggested as an attractive strategy for inducing apoptosis in AML LSCs. However, the selective inhibition of Bcl-2 in AML often leads to upregulation of Mcl-1, another dominant anti-apoptotic Bcl-2 family protein conferring venetoclax resistance. Methods We assessed the combined effect of venetoclax and arsenic trioxide (ATO) on leukaemic cell viability, apoptosis, combination index, and cell cycle in the human LSC-like KG1 and KG1a cells. The synergistic effect of venetoclax and ATO on apoptosis was also examined in primary CD34+ and CD34+CD38− LSCs from the bone marrow (BM) of AML patients, and compared with those from healthy donors. Results Venetoclax efficiently impaired cell viability and dose-dependently promoted apoptosis when combined with ATO; their synergism was aptly represented by the combination index. The combination of venetoclax and ATO impaired cell cycle progression by restricting cells within the sub-G1 phase and facilitating caspase-dependent apoptotic cell death associated with the loss of mitochondrial membrane potential, while sparing healthy BM haematopoietic stem cells. Mechanistically, ATO mitigated venetoclax-induced upregulation of Mcl-1 by the inhibition of AKT and ERK, along with activation of GSK-3β. This led to the Mcl-1 destabilisation, triggering Noxa and Bim to facilitate apoptosis and the consequent activation of the apoptosis executioner protein Bak. Moreover, the combination promoted phosphorylation of ATM, Chk2, p38, and H2AX, indicating an active DNA damage response. Conclusions Our findings demonstrate the synergistic, preferential antileukaemic effects of venetoclax and ATO on LSCs, providing a rationale for preclinical and clinical trials by combining these agents already being used in clinical practice to treat acute leukaemia.

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“…Homeostasis of healthy HSCs is regulated by oxidative phosphorylation (OXPHOS)-driven regeneration and glycolysis-mediated quiescence (61). This balance is dysregulated in AML LSCs, as LSCs preferentially depend on mitochondrial OXPHOS to a greater degree than on glycolysis (5). Considering that ATO activates quiescent HSCs and LSCs (62), the simultaneous inhibition of increased mitochondrial OXPHOS by venetoclax and unleashing LSC quiescence by ATO could have cooperatively sensitised LSCs to the combination treatment while sparing healthy HSCs.…”

Section: Discussionmentioning

confidence: 99%

Arsenic Trioxide Synergistically Promotes the Antileukaemic Activity of Venetoclax by Downregulating Mcl-1 in Acute Myeloid Leukaemia Cells

Cho

Jang

Eom

et al. 2020

Preprint

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BackgroundThe evasion of apoptosis through dysregulated Bcl-2 family members is a hallmark of leukaemia stem cells (LSCs) in acute myeloid leukaemia (AML). Therefore, targeting Bcl-2 with venetoclax has been suggested as an attractive strategy for inducing apoptosis in AML LSCs. However, the selective inhibition of Bcl-2 in AML often leads to upregulation of Mcl-1, another dominant anti-apoptotic Bcl-2 family protein conferring venetoclax resistance.MethodsWe assessed the combined effect of venetoclax and arsenic trioxide (ATO) on leukaemic cell viability, apoptosis, combination index, and cell cycle in the human LSC-like KG1 and KG1a cells. The synergistic effect of venetoclax and ATO on apoptosis was also examined in primary CD34+ and CD34+CD38- LSCs from the bone marrow (BM) of AML patients, and compared with those from healthy donors.ResultsVenetoclax efficiently impaired cell viability and dose-dependently promoted apoptosis when combined with ATO; their synergism was aptly represented by the combination index. The combination of venetoclax and ATO impaired cell cycle progression by restricting cells within the sub-G1 phase and facilitating caspase-dependent apoptotic cell death associated with the loss of mitochondrial membrane potential, while sparing healthy BM haematopoietic stem cells. Mechanistically, ATO mitigated venetoclax-induced upregulation of Mcl-1 by the inhibition of AKT and ERK, along with activation of GSK-3β. This led to the Mcl-1 destabilisation, triggering Noxa and Bim to facilitate apoptosis and the consequent activation of the apoptosis executioner protein Bak. Moreover, the combination promoted phosphorylation of ATM, Chk2, p38, and H2AX, indicating an active DNA damage response.ConclusionsOur findings demonstrate the synergistic, preferential antileukaemic effects of venetoclax and ATO on LSCs, providing a rationale for preclinical and clinical trials by combining these agents already being used in clinical practice to treat acute leukaemia.

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Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis

Cited by 120 publications

References 198 publications

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukaemia cells

Arsenic Trioxide Synergistically Promotes the Antileukaemic Activity of Venetoclax by Downregulating Mcl-1 in Acute Myeloid Leukaemia Cells

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