Related Experiment Video

Updated: May 16, 2025

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
14:51

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

3.1K

Enhancer Extrachromosomal Circular DNA ANKRD28 Elicits Drug Resistance via POU2F2-Mediated Transcriptional Network in

Binzhen Chen1, Jia Liu1, Yaoxin Zhang2,3

  • 1Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 1, 2025
PubMed

Insights

Extrachromosomal circular DNA ANKRD28 (eccANKRD28) drives multiple myeloma drug resistance by activating oncogenes. Targeting eccANKRD28 may improve treatment outcomes for patients with this incurable cancer.

Area of Science:

  • Genomics
  • Epigenetics
  • Cancer Biology

Background:

  • Multiple myeloma (MM) is an incurable blood cancer characterized by drug resistance.
  • Extrachromosomal circular DNAs (eccDNAs) are found in cancer genomes, but their role as enhancers in non-coding regions is understudied.
  • Mechanisms of drug resistance in MM remain unclear.

Purpose of the Study:

  • To investigate the role of non-coding eccDNAs, specifically enhancer eccDNAs, in multiple myeloma drug resistance.
  • To characterize serum eccDNAs in MM patients with varying responses to bortezomib-lenalidomide-dexamethasone (VRd) therapy.
  • To identify novel epigenetic mechanisms contributing to therapeutic failure in MM.

Main Methods:

  • Genome-wide profiling of serum eccDNAs from MM patients and healthy donors.
  • Analysis of eccDNA abundance in VRd-sensitive and VRd-resistant MM cell lines.
  • CRISPR/Cas9-mediated manipulation of eccANKRD28 levels.
  • Integrated multi-omics analyses including ChIP-seq, scRNA-seq, and scATAC-seq.
  • Identification of transcription factor interactions and target oncogenes.

Main Results:

  • A high copy number of eccDNA ANKRD28 (eccANKRD28) was associated with poor VRd therapy response and prognosis.
  • VRd-resistant MM cell lines showed increased eccANKRD28 abundance.
  • Elevating eccANKRD28 desensitized MM cells to bortezomib and lenalidomide in vitro and in vivo.
  • eccANKRD28 functions as an active enhancer regulated by POU class 2 homeobox 2 (POU2F2).
  • POU2F2, with RUNX1/RUNX2, activates oncogene promoters (IRF4, JUNB, IKZF3, RUNX3, BCL2).

Conclusions:

  • eccANKRD28 is a key enhancer driving multiple myeloma drug resistance.
  • The POU2F2-eccANKRD28 regulatory network represents a novel epigenetic mechanism in MM therapeutic failure.
  • Targeting eccANKRD28 and its associated transcriptional network offers a potential strategy to overcome drug resistance in MM.
Keywords:
drug resistanceenhancerextrachromosomal circular DNAmultiple myelomatranscriptional regulation

More Related Videos

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence10:09

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

8.2K
Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models09:58

Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models

Published on: December 9, 2016

13.6K

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.2K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.4K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
3.9K
Cell Specific Gene Expression01:58

Cell Specific Gene Expression

Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
13.3K
Master Transcription Regulators02:23

Master Transcription Regulators

Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.8K
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
3.0K