Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Grønningsæter, Ida Sofie; Reikvam, Håkon; Aasebø, Elise; Bartaula-Brevik, Sushma; Tvedt, Tor Henrik Andersson; Bruserud, Øystein; Hatfield, Kimberley Joanne

doi:10.3390/cells9051155

Cited by 27 publications

(36 citation statements)

References 67 publications

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“…55 In recent years, many studies have shown that treatment with metformin inhibits the growth of tumor cells by activating the AMPK/mTOR, thereby promoting autophagy. 56,57 Additionally, metformin alters the chromatin structure that regulates the function of enzymes such as CBP/P300, SIRT1, and HAT1, which are involved in histone acetylation. [58][59][60] We found that metformin reduces B7-H6 expression, to a similar extent to JQ1, by modulating acetylation patterns in the B7-H6 promoter.…”

Section: Discussionmentioning

confidence: 99%

Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia

et al. 2021

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B7-H6, a ligand for the NK activating receptor NKp30, has been identified as a biomarker of poor prognosis in several solid cancers. However, little is known about the role of B7-H6 and the mechanisms that control its expression in acute myeloid leukemia (AML). Epigenome modulation, including epigenomic reader dysregulation, is one of the hallmarks of AML. Bromodomain-containing protein 4 (BRD4), the best-known member of the BET family of epigenetic readers, is overexpressed in AML cells and regulates the transcription of genes involved in the pathogenesis of AML, as MYC oncogene. Here, we analyze the role of BRD4 in regulating B7-H6 in AML cells. Results demonstrated that the specific inhibition of BRD4 drastically reduces the expression of B7-H6 in AML cells. Histone acetylation mediated by CBP30/P300 facilitates the binding of BRD4 to the B7-H6 promoter, which recruits the P -TEFb elongation factor that phosphorylates RNA polymerase II, thereby activating B7-H6 transcription. BRD4 also co-bounded with JMJD6 at the distal enhancer of the B7-H6 gene. Metabolic modulation with metformin modifies the acetylation pattern in the B7-H6 promoter, impairing BRD4 binding, thereby inhibiting B7-H6 expression. B7-H6 knockdown induces the apoptosis in HEL-R cell line. Moreover, a high level of B7-H6 expression in AML patients is related to increased BRD4 levels, myelodysplastic-derived AML, and del5q, the two latter being associated with poor prognosis. Our data show that BRD4 is a positive regulator of the pro-tumorigenic molecule B7-H6 and that the blockage of the B7-H6 is a potential therapeutic target for the treatment of AML.

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Section: Discussionmentioning

confidence: 99%

Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia

et al. 2021

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“…Second, another subset of genes encoded proteins that are important for mitochondrial functions, and thereby, probably also for the regulation of cellular metabolism. The targeting of mitochondria or cellular metabolism is now regarded as a possible therapeutic strategy in human AML [ 48 , 49 , 50 , 51 ]. Third, several downregulated genes encoded interacting proteins that are important for the spliceosome or RNA binding/transport.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

Reikvam

2020

Cells

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Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.

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“…AML is a very heterogeneous disease and this heterogeneity has been demonstrated both by cytogenetic and molecular genetic analyses as well as gene expression, epigenetic, and possibly also proteomic and metabolic profiling [ 12 , 43 , 44 , 45 , 46 , 47 , 48 ]. The most important factors for evaluation of AML relapse risk in routine clinical practice are the cytogenetic and the molecular genetic abnormalities (these and other prognostic factors are gathered in Table 1 ).…”

Section: Aml Heterogeneity and Prognostic Evaluationmentioning

confidence: 99%

“…A large clinical study showed that the systemic levels of 14 glucose metabolites could be used to identify patients with an increased risk of later leukemia relapse [ 51 ]. Other studies also suggest that the AML cell metabolism and not only the systemic metabolic regulation differ between AML patients [ 48 , 67 , 68 ], but the possible prognostic impact of such differences needs further investigation.…”

Section: Aml Heterogeneity and Prognostic Evaluationmentioning

confidence: 99%

“…First, early morphological disease control with remission induction (but remaining MRD) is an important prognostic parameter [ 13 , 14 , 73 , 74 ] and this is a characteristic of the total AML cell population. Second, a large number of clinical studies have shown that biological characteristics of the total AML cell population reflect fundamental cell population characteristics that have a prognostic impact and are essential for leukemogenesis/chemosensitivity [ 43 , 44 , 46 , 47 , 48 ]. Third, previous studies have shown that the AML stem cells can be detected in various subsets, usually CD34 + CD38 − but also CD34 − and CD34 + CD38 + cells [ 65 , 75 , 76 ].…”

Section: Aml Heterogeneity and Prognostic Evaluationmentioning

confidence: 99%

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The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

Hernandez-Valladares

Bruserud

Selheim

2020

IJMS

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With the current reproducibility of proteome preparation workflows along with the speed and sensitivity of the mass spectrometers, the transition of the mass spectrometry (MS)-based proteomics technology from biomarker discovery to clinical implementation is under appraisal in the biomedicine community. Therefore, this technology might be implemented soon to detect well-known biomarkers in cancers and other diseases. Acute myeloid leukemia (AML) is an aggressive heterogeneous malignancy that requires intensive treatment to cure the patient. Leukemia relapse is still a major challenge even for patients who have favorable genetic abnormalities. MS-based proteomics could be of great help to both describe the proteome changes of individual patients and identify biomarkers that might encourage specific treatments or clinical strategies. Herein, we will review the advances and availability of the MS-based proteomics strategies that could already be used in clinical proteomics. However, the heterogeneity of complex diseases as AML requires consensus to recognize AML biomarkers and to establish MS-based workflows that allow their unbiased identification and quantification. Although our literature review appears promising towards the utilization of MS-based proteomics in clinical AML in a near future, major efforts are required to validate AML biomarkers and agree on clinically approved workflows.

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Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Cited by 27 publications

References 67 publications

Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia

Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

The Implementation of Mass Spectrometry-Based Proteomics Workflows in Clinical Routines of Acute Myeloid Leukemia: Applicability and Perspectives

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