Histone variants:critical determinants in tumour heterogeneity

Malignant cell transformation could be considered as a series of cell reprogramming events driven by oncogenic transcription factors and upstream signalling pathways.Chromatin plasticity and dynamics are critical determinants in the control of cell reprograming.An increase in chromatin dynamics could therefore constitute an essential step in driving oncogenesis and in generating tumour cell heterogeneity,which is indispensable for the selection of aggressive properties,including the ability of cells to disseminate and acquire resistance to treatments.Histone supply and dosage,as well as histone variants,are the best-known regulators of chromatin dynamics.By facilitating cell reprogramming,histone under-dosage and histone variants should also be crucial in cell transformation and tumour metastasis.Here we summarize and discuss our knowledge of the role of histone supply and histone variants in chromatin dynamics and their ability to enhance oncogenic cell reprogramming and tumour heterogeneity.

Current treatment strategy of acute promyelocytic leukemia

Acute promyelocytic leukemia(APL)is a unique subtype of acute myeloid leukemia(AML).The prognosis of APL has changed from the worst among the AMLs to currently the best.The application of all-trans retinoic acid(ATRA)in the induction therapy of APL decreases the high mortality of newly diagnosed patients,thereby significantly improving the response rate.ATRA combined with anthracycline-based chemotherapy is the current standard treatment,and for high-risk patients,high doses cytarabine have a beneficial effect on relapse prevention.In recent years,the indications of arsenic trioxide(ATO)therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL.The introduction of both ATRA and ATO represents great achievements in translational medicine.In this review article,we discuss the therapeutic strategies for this disease,including the initial approaches to newly diagnosed patients,prevention,and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

DNA crosslinking and recombination-activating genes 1/2(RAG1/2)are required for oncogenic splicing in acute lymphoblastic leukemia

Background:Abnormal alternative splicing is frequently associated with carcinogenesis.In B-cell acute lymphoblastic leukemia(B-ALL),double homeobox 4 fused with immunoglobulin heavy chain(DUX4/IGH)can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript(ERGalt)and other splicing variants.However,the molecular mechanism underpinning this process remains elusive.Here,we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia.Methods:The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients.X-ray crystallography,small angle X-ray scattering(SAXS),and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element(DRE)-DRE sites.The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity.To check whether recombination-activating gene 1/2(RAG1/2)was required for DUX4/IGH-driven splicing,the proximity ligation assay,co-immunoprecipitation,mammalian two hybrid characterizations,in vitro RAG1/2 cleavage,and shRNA knock-down assays were performed.Results:We reported previously unrecognized intron retention events in Ctype lectin domain family 12,member A abnormal transcript(CLEC12Aalt)and chromosome 6 open reading frame 89 abnormal transcript(C6orf89alt),where also harbored repetitive DRE-DRE sites.Supportively,X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain(HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites.Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt,CLEC12Aalt,and C6orf89alt biogenesis,resulting in marked alleviation of its inhibitory effect on B-cell differentiation.Furthermore,we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes.Supportively,shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt,CLEC12Aalt,and C6orf89alt.Conclusions:All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites,catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia.