The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

Xiao, Lin; Karsa, Mawar; Ronca, Emma; Bongers, Angelika; Kosciolek, Angelika; El-Ayoubi, Ali; Revalde, Jezrael L.; Seneviratne, Janith A.; Cheung, Belamy B.; Cheung, Laurence C.; Kotecha, Rishi S.; Newbold, Andrea; Bjelosevic, Stefan; Arndt, Greg M.; Lock, Richard B.; Johnstone, Ricky W.; Gudkov, Andrei V.; Gurova, Katerina V.; Haber, Michelle; Norris, Murray D.; Henderson, Michelle J.; Somers, Klaartje

doi:10.3389/fonc.2022.863329

Cited by 8 publications

(8 citation statements)

References 35 publications

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“…Curaxin CBL0137 inhibits KMT2A -r leukemia cell growth by rapidly inducing apoptosis, and the addition of HDAC increased CBL0137-induced apoptosis. Similar effects were obtained after using CBL0137 in combination with another HDAC inhibitor, entinostat [ 84 , 85 ].…”

Section: Potential Therapeutic Targetssupporting

confidence: 69%

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

et al. 2023

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The KMT2A (formerly MLL) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. KMT2A is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 KMT2A fusion partners have been identified until now, including the most recurring ones—AFF1, MLLT1, and MLLT3—which encode proteins regulating epigenetic mechanisms. The presence of distinct KMT2A rearrangements is an independent dismal prognostic factor, while very few KMT2A rearrangements display either a good or intermediate outcome. KMT2A-rearranged (KMT2A-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5–6% of pediatric cases, and 15% of adult cases. KMT2A-rearranged (KMT2A-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with KMT2A ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of KMT2A-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.

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Section: Potential Therapeutic Targetssupporting

confidence: 69%

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

et al. 2023

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“…CBL0137 [1,1′-(9-(2-(isopropylamino)ethyl)-9H-carbazole-3,6-diyl)bis(ethan-1-one)] is a low-molecular-weight nongenotoxic DNA-binding compound from the class of carbazoles referred to as the second generation of Curaxines [ 12 ]. CBL0137 possesses a broad spectrum of anticancer effects, which was confirmed in more than 50 preclinical studies [ 13 , 14 , 15 , 16 , 17 ]. Currently, CBL0137 is involved in Phase I-II clinical trials for the treatment of glioblastoma, melanoma, sarcoma, lymphoma, and some other types of cancer (NCT04870944, NCT03727789, and NCT05498792).…”

Section: Introductionmentioning

confidence: 93%

Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins

Maksimova,

Popova,

Prus

et al. 2023

IJMS

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The development of malignant tumors is caused by a complex combination of genetic mutations and epigenetic alterations, the latter of which are induced by either external environmental factors or signaling disruption following genetic mutations. Some types of cancer demonstrate a significant increase in epigenetic enzymes, and targeting these epigenetic alterations represents a compelling strategy to reverse cell transcriptome to the normal state, improving chemotherapy response. Curaxin CBL0137 is a new potent anticancer drug that has been shown to activate epigenetically silenced genes. However, its detailed effects on the enzymes of the epigenetic system of transcription regulation have not been studied. Here, we report that CBL0137 inhibits the expression of DNA methyltransferase DNMT3a in HeLa TI cells, both at the level of mRNA and protein, and it decreases the level of integral DNA methylation in Ca Ski cells. For the first time, it is shown that CBL0137 decreases the level of BET family proteins, BRD2, BRD3, and BRD4, the key participants in transcription elongation, followed by the corresponding gene expression enhancement. Furthermore, we demonstrate that CBL0137 does not affect the mechanisms of histone acetylation and methylation. The ability of CBL0137 to suppress DNMT3A and BET family proteins should be taken into consideration when combined chemotherapy is applied. Our data demonstrate the potential of CBL0137 to be used in the therapy of tumors with corresponding aberrant epigenetic profiles.

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“…Due to these two processes, CBL0137 and panobinostat decondensed chromatin, respectively, which leads to downstream anti-cancer processes. This combination causes a limit of progression and extends the survival time in the mouse model [ 54 ]. Romidepsin also showed efficiency in MLL-rearranged ALL.…”

Section: Modifications Of Histones In Pediatric Allmentioning

confidence: 99%

A Comprehensive Overview of Recent Advances in Epigenetics in Pediatric Acute Lymphoblastic Leukemia

Drożak

Bryliński

Zawitkowska

2022

Cancers

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Recent years have brought a novel insight into our understanding of childhood acute lymphoblastic leukemia (ALL), along with several breakthrough treatment methods. However, multiple aspects of mechanisms behind this disease remain to be elucidated. Evidence suggests that leukemogenesis in ALL is widely influenced by epigenetic modifications. These changes include: DNA hypermethylation, histone modification and miRNA alteration. DNA hypermethylation in promoter regions, which leads to silencing of tumor suppressor genes, is a common epigenetic alteration in ALL. Histone modifications are mainly caused by an increased expression of histone deacetylases. A dysregulation of miRNA results in changes in the expression of their target genes. To date, several hundred genes were identified as suppressed by epigenetic mechanisms in ALL. What is promising is that epigenetic alterations in ALL may be used as potential biomarkers for classification of subtypes, predicting relapse and disease progression and assessing minimal residual disease. Furthermore, since epigenetic lesions are potentially reversible, an activation of epigenetically silenced genes with the use of hypomethylating agents or histone deacetylase inhibitors may be utilized as a therapeutic strategy for ALL. The following review summarizes our current knowledge about epigenetic modifications in ALL and describes potential uses of epigenetics in the clinical management of this disease.

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The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

Cited by 8 publications

References 35 publications

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia

Insights into the Mechanism of Curaxin CBL0137 Epigenetic Activity: The Induction of DNA Demethylation and the Suppression of BET Family Proteins

A Comprehensive Overview of Recent Advances in Epigenetics in Pediatric Acute Lymphoblastic Leukemia

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