Targeting Chromatin Regulation in Acute Myeloid Leukemia

Richardson, Simon; Huntly, Brian J. P.

doi:10.1097/hs9.0000000000000589

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…Thus, chromatin regulation is a critical target in AML. [35] Furthermore, our kinase-substrate analysis identified AURKB, a serine/threonine kinase involved in mitosis regulation, which has been reported to be a potential inducer of DA resistance contributing to tumor progression and drug resistance in solid ). E) The cell viability of mock and AURKB-overexpressing THP-1 or U937 cells was analyzed after treatment with the indicated drugs for 48 h (n = 3 replicates per sample).…”

Section: Discussionmentioning

confidence: 86%

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia

Jin,

Hou,

Yao

et al. 2023

Advanced Science

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Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV‐sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV‐susceptible and DA‐resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA‐resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL‐1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.

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Section: Discussionmentioning

confidence: 86%

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia

Jin,

Hou,

Yao

et al. 2023

Advanced Science

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“…For example, some epigenetic modifying agents, including Tazemetostat, GSK126, and UNC199 were developed to control the oncogenic role of EZH2 [ 125 ]. Pinometostat represents a DOT1L inhibitor that has shown therapeutic potential for cases of acute leukemias involving mixed lineage leukemia (MLL) gene rearrangements [ 126 ]. The therapeutic strategy of epigenetic modulation could represent a considerable advance for personalized medicine.…”

Section: Glp and G9a As Therapeutic Targetsmentioning

confidence: 99%

GLP and G9a histone methyltransferases as potential therapeutic targets for lymphoid neoplasms

Silva-Carvalho,

Filiú-Braga,

Bogéa

et al. 2024

Cancer Cell Int

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Histone methyltransferases (HMTs) are enzymes that regulate histone methylation and play an important role in controlling transcription by altering the chromatin structure. Aberrant activation of HMTs has been widely reported in certain types of neoplastic cells. Among them, G9a/EHMT2 and GLP/EHMT1 are crucial for H3K9 methylation, and their dysregulation has been associated with tumor initiation and progression in different types of cancer. More recently, it has been shown that G9a and GLP appear to play a critical role in several lymphoid hematologic malignancies. Importantly, the key roles played by both enzymes in various diseases made them attractive targets for drug development. In fact, in recent years, several groups have tried to develop small molecule inhibitors targeting their epigenetic activities as potential anticancer therapeutic tools. In this review, we discuss the physiological role of GLP and G9a, their oncogenic functions in hematologic malignancies of the lymphoid lineage, and the therapeutic potential of epigenetic drugs targeting G9a/GLP for cancer treatment.

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Targeting Chromatin Regulation in Acute Myeloid Leukemia

Cited by 2 publications

References 27 publications

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia

GLP and G9a histone methyltransferases as potential therapeutic targets for lymphoid neoplasms

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