Leukemia, the blood cancer, is a group ofhematopoietic malignancies. Many types of leukemia are associated with pooroutcome. Unfortunately, during the past a few decades, the first-line leukemiatherapy has long been traditional chemotherapy with high cytotoxicity and lowselectivity, such as the “7+3” strategy, i.e., a combination of cytarabine anddoxorubicin. Also, side effects of such intensive chemotherapies are oftensevere, especially in elder patients. Therefore, it is in urgent need tounderstand the mechanisms of leukemia, and develop novel targeted therapy basedon such comprehension.

The Ten-eleven translocation (TET) mediatedDNA 5-hydroxymethlcytosine (5hmC) modification is a kind of epigeneticregulation, which regulates gene expression and function through subtle modificationswithout changing the genetic codes. In recent years, Dr. JIANG Xi of School ofMedicine, Zhejiang University, and her colleagues have been making continuousefforts in the research field of leukemia epigenetics, and has contributed aseries of important discoveries. In their previous publications, theysuccessfully unveiled the role and regulatory mechanisms of TET genes in acutemyeloid leukemia (AML).

Recently, the research group led by Dr.Jiang published an article entitled “Opioid receptor signaling suppressesleukemia through both catalytic and non-catalytic functions of TET2” in thejournal Cell Reports.

In this work, Jiang’s group first foundthrough drug screening that opioid receptor agonists, especially loperamide(OPA1), an FDA-approved anti-diarrhea drug, remarkably suppressed the viabilityof AML cells. The therapeutic effect of OPA1 was then verified in mouse modelsrepresenting different AML subtypes, as well as in a patient derived model(patient derived xenotransplantation, PDX) in which AML patient bone marrowcells were transplanted into immunodeficient mice (Fig. 1).

Fig. 1 Therapeutic effects of OPA1 in AML.

Through an integration of genome-wideRNA-seq, 5hmC-seq, chromosome immunoprecipitation (ChIP)-seq and othermechanism studies, the authors show that OPA1 activated opioid receptorsignaling, recruited transcription factors, e.g. EGR1, to the promoter of TET2gene, and upregulated TET2 expression. TET2, as a key factor of DNA epigeneticmodification, then functioned in both activity dependent and independent ways.On one hand, it mediated the 5hmC modification of its target genes, e.g. TRAF2;on the other hand, it recruited OGT to their shared targets, e.g. DNMT. Thus,the OPA1/opioid signaling/TET2 axis plays an important role in regulating theexpression of the target genes, and curing leukemia (Fig. 2).