Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

Perner, Florian; Armstrong, Scott A.

doi:10.3390/cells9122721

Cited by 15 publications

(11 citation statements)

References 243 publications

(333 reference statements)

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“…Thus, these results suggest that the development of a small molecule inhibitor targeting this kinase could be useful to treat MLL-rearranged leukemias. For example, a combination therapy with inhibitors of DOT1L or of the DOT1L/MENIN interaction, that are in clinical trials for the treatment of MLL-r acute leukemias 105 , could be an exciting new therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Oliveira¹,

Zhang²,

Joo³

et al. 2021

Theranostics

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B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi- omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi- omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi- omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.

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Section: Discussionmentioning

confidence: 99%

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Oliveira¹,

Zhang²,

Joo³

et al. 2021

Theranostics

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“…BET proteins play significant roles in human oncogenesis. Emerging anti-cancer small molecule inhibitors rely on acetylation mimics which block the BET bromodomains from binding chromatin (Alqahtani et al, 2019;Cochran et al, 2019;Zaware and Zhou, 2019;Lu et al, 2020;Perner and Armstrong, 2020). For example, archetypical compounds I-BET and JQ-1 were shown to bind the BET bromodomains and disrupt SE function in myeloid leukemia (Zuber et al, 2011;Loven et al, 2013).…”

Section: Integration Site Selection In Cellsmentioning

confidence: 99%

Strategies for Targeting Retroviral Integration for Safer Gene Therapy: Advances and Challenges

Yoder

Rabe

Fishel

et al. 2021

Front. Mol. Biosci.

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Retroviruses are obligate intracellular parasites that must integrate a copy of the viral genome into the host DNA. The integration reaction is performed by the viral enzyme integrase in complex with the two ends of the viral cDNA genome and yields an integrated provirus. Retroviral vector particles are attractive gene therapy delivery tools due to their stable integration. However, some retroviral integration events may dysregulate host oncogenes leading to cancer in gene therapy patients. Multiple strategies to target retroviral integration, particularly to genetic safe harbors, have been tested with limited success. Attempts to target integration may be limited by the multimerization of integrase or the presence of host co-factors for integration. Several retroviral integration complexes have evolved a mechanism of tethering to chromatin via a host protein. Integration host co-factors bind chromatin, anchoring the complex and allowing integration. The tethering factor allows for both close proximity to the target DNA and specificity of targeting. Each retrovirus appears to have distinct preferences for DNA sequence and chromatin features at the integration site. Tethering factors determine the preference for chromatin features, but do not affect the subtle sequence preference at the integration site. The sequence preference is likely intrinsic to the integrase protein. New developments may uncouple the requirement for a tethering factor and increase the ability to redirect retroviral integration.

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“…Cancer cells often acquire tumor-specific SEs at vital oncogenes, such as MYC, which induce several hallmarks of cancer. Bromodomain-containing protein 4 (BRD4), a member of the bromodomains and extra-terminal (BET) protein family [16][17][18][19], binds to acetylated H3 lysine 27 (H3K27ac) on chromatin, where transcription regulators are recruited to form multi-molecular assemblies [20,21]. BRD4 is recruited to SEs and consequently functions as an epigenetic reader to promote the transcription of SE-marked genes in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

Kondo

Mishiro

Iwashima

et al. 2022

Cells

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Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family.

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Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

Cited by 15 publications

References 243 publications

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia

Strategies for Targeting Retroviral Integration for Safer Gene Therapy: Advances and Challenges

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

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