Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia

Zee, Barry M.; Poels, Kamrine E.; Yao, Cong-Hui; Kawabata, Kimihito C.; Wu, Gongwei; Duy, Cihangir; Jacobus, William D.; Senior, Elizabeth; Endress, Jennifer E.; Jambhekar, Ashwini; Lovitch, Scott B.; Ma, Jiexian; Dhall, Abhinav; Harris, Isaac S.; Blanco, Mario Andres; Sykes, David B.; Licht, Jonathan D.; Weinstock, David M.; Melnick, Ari; Haigis, Marcia C.; Michor, Franziska; Shi, Yang

doi:10.1016/j.isci.2021.102651

Cited by 5 publications

(4 citation statements)

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“…To examine how these changes are related to chromatin accessibility and to nominate transcription factor programs that might drive these changes, we performed a timecourse of ATAC-seq after BRQ treatment or E2 withdrawal in ER-Hoxa9 cells. Chromatin accessibility changes were skewed towards gains in accessibility in BRQ and enriched at introns and intergenic regions (Figure 6J, S7K), consistent with enhancers playing important roles in driving cell fate progression (Blanco et al 2021). Similar patterns were observed in THP-1 cells treated with BRQ or PMA for 24 or 48 hours (Figure 6K, S7L).…”

Section: Expression Changes Coincide With Changes In Chromatin State ...supporting

confidence: 62%

“…Inhibitors of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) have been identified as a novel class of differentiation agents in non-promyelocytic and non-IDH mutated AML (Sykes et al, 2016). As a result, DHODH inhibitors are currently being evaluated for the treatment of AML and other cancers (Christian et al, 2019; Zee et al, 2021). These studies raise the question of how pyrimidine depletion can induce a cell fate change and, more broadly, whether other therapeutic strategies that target metabolism might be similarly effective.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibitors of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) were previously identified as a novel class of differentiation agents in non-promyelocytic and non-IDH mutated AML (Sykes et al, 2016). As a result, DHODH inhibitors may be effective for the treatment of AML and other cancers (Christian et al, 2019; Zee et al, 2021). Nevertheless, the mechanism by which pyrimidine depletion can induce differentiation remains unclear, and whether perturbing other metabolic enzymes and pathways might also influence lineage-specific gene expression changes in cells remains an open question.…”

Section: Introductionmentioning

confidence: 99%

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Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Hsu

Brian

Vermeulen

et al. 2022

Preprint

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Control of cellular identity involves coordination of developmental programs with environmental factors such as nutrient availability, suggesting that modulating aspects of metabolism could enable therapeutically relevant changes in cell fate. We show that nucleotide depletion facilitates gene expression changes towards a new cell fate by perturbing DNA replication in models of acute myeloid leukemia, a cancer characterized by a differentiation blockade. This transition starts in S phase and is independent of replication stress signaling and DNA damage signaling pathways. Moreover, it occurs despite sustained oncogene-driven expression of the progenitor program and is accompanied by limited changes in chromatin accessibility. Altering lineage-determining transcription factor expression redirects cell fate progression towards an alternate fate upon replication stress, suggesting that perturbing DNA replication allows cells to mobilize primed maturation programs. Our work, along with other findings in diverse systems, suggests a conserved mechanism by which metabolic changes can orchestrate cell fate transitions.

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Section: Expression Changes Coincide With Changes In Chromatin State ...supporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Hsu

Brian

Vermeulen

et al. 2022

Preprint

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“…It is a clonal malignancy of myeloid progenitor cells that maintain a hyperproliferative, undifferentiated state and survive by inhibiting apoptosis [67,68]. This cell differentiation inhibition has been associated with the disruption of several cellular processes, including transcriptional, chromatin, and metabolic regulation [69].…”

Section: Targeting Lipid Droplets In Acute Myeloid Leukemiamentioning

confidence: 99%

An Overview on Lipid Droplets Accumulation as Novel Target for Acute Myeloid Leukemia Therapy

Nisticò,

Chiarella

2023

Biomedicines

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Metabolic reprogramming is a key alteration in tumorigenesis. In cancer cells, changes in metabolic fluxes are required to cope with large demands on ATP, NADPH, and NADH, as well as carbon skeletons. In particular, dysregulation in lipid metabolism ensures a great energy source for the cells and sustains cell membrane biogenesis and signaling molecules, which are necessary for tumor progression. Increased lipid uptake and synthesis results in intracellular lipid accumulation as lipid droplets (LDs), which in recent years have been considered hallmarks of malignancies. Here, we review current evidence implicating the biogenesis, composition, and functions of lipid droplets in acute myeloid leukemia (AML). This is an aggressive hematological neoplasm originating from the abnormal expansion of myeloid progenitor cells in bone marrow and blood and can be fatal within a few months without treatment. LD accumulation positively correlates with a poor prognosis in AML since it involves the activation of oncogenic signaling pathways and cross-talk between the tumor microenvironment and leukemic cells. Targeting altered LD production could represent a potential therapeutic strategy in AML. From this perspective, we discuss the main inhibitors tested in in vitro AML cell models to block LD formation, which is often associated with leukemia aggressiveness and which may find clinical application in the future.

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Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Do,

Hsu,

Vermeulen

et al. 2024

Developmental Cell

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Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia

Abstract: Combined epigenetic and metabolic perturbations induce myeloid differentiationCombination treatment alters nucleotide, lipid, and gene expression profiles Combination treatment induces differentiation of human acute myeloid leukemia cells

Cited by 5 publications

References 77 publications

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

An Overview on Lipid Droplets Accumulation as Novel Target for Acute Myeloid Leukemia Therapy

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

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