Recent advances in acute promyelocytic leukaemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Ng CH
PROVIDER: S-EPMC5538034 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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| S-EPMC9270575 | biostudies-literature
Project description:In the past few years, research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML, facilitated by next-generation sequencing, has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Various new agents, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific T-cell engager antibodies, metabolic and pro-apoptotic agents are currently investigated within clinical trials. The highest response rates are often achieved when new molecularly targeted therapies are combined with standard chemotherapy. Presented here is an overview of novel therapies currently being evaluated in AML.
| S-EPMC5801209 | biostudies-literature
Project description:The PML-RAR? fusion gene, generated by the t(15;17) chromosome translocation, is regarded as the initiating factor of acute promyelocytic leukaemia (APL). In addition to the well-known effects on blocking myeloid differentiation at the promyelocytic stage, promyelocytic leukaemia-retinoic acid receptor ? (PML-RAR?) has also been reported to interfere with multiple differentiation processes, including erythroid differentiation. However, the detailed molecular mechanism by which PML-RAR? impairs erythropoiesis has not yet been fully addressed. By chromatin immunoprecipitation-PCR assay, we found that PML-RAR? bound to the distal promoter region of LMO2 (LIM-only protein 2), a critical erythroid-specific transcription factor. Luciferase reporter assays and qRT-PCR results demonstrated that PML-RAR? down-regulated the expression of the LMO2 distal transcript through transrepressing its promoter activity. Analysis of gene expression profiling data from large cohorts of acute myeloid leukaemia (AML) patients confirmed that LMO2 expressed at a markedly lower level in APL patients in comparison to non-APL AML patients. Further flow cytometry analysis demonstrated that PML-RAR? inhibited erythropoietin-induced erythroid differentiation by down-regulating LMO2 expression. Our findings reveal a previously unidentified mechanism, by which PML-RAR? interferes with erythropoiesis through directly targeting and transrepressing LMO2 expression in the development of APL.
| S-EPMC6237603 | biostudies-literature
Project description:RationaleThe vast majority of acute promyelocytic leukemia (APL) is characterized with a specific chromosomal translocation t (15, 17) (q22, q21), which fuses PML-RARα leading to a good response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, there are few cases of atypical APL, including PLZF-RARα, F1P1L1-RARα, STAT5b-RARα, et al. Neither PLZF-RARα nor STAT5b-RARα are sensitive to ATRA and ATO, and the prognosis is poor.Patient concernsHere we have 3 cases (PLZF-RARα, n = 2; STAT5b-RARα, n = 1). Case A, A 53-year-old Chinese female had suffered ecchymosis in both legs for 3 days. Case B, A 44 years old male suffered pain from lower limbs and hip. Case C, 52-year-old male patient presented with fever for 3 weeks invalid to antibiotics and gingival bleeding for 1 week.DiagnosesWith RT-PCR and karyotype, Case A is diagnosed with STAT5b-RARα-positive APL.Case B, C are diagnosed with PLZF-RARα-positive APL.InterventionsIn case A, ATO, and ATRA were used for induction treatment. In Case B, ATO, and chemotherapy with DA were given in the first induction treatment. In Case C, ATRA, and ATO were used immediately, subsequently, chemotherapy was added with DA, ATRA, and CAG combination treatment, and medium-dose cytarabine with daunorubicin were given regularly.OutcomesIn Case A, the patient refused the following treatment and discharged on day 25. In Case B, the patient got the disseminated intravascular coagulation (DIC).In Case C, the patient has survived for 7 months and remains CR.LessonsBoth STAT5b-RARα-positive APL and PLZF-RARα-positive APL appear to be resistant to both ATRA and ATO, so combined chemotherapy and allo-HSCT should be considered. Since the prognosis and long-term outcome are poor, more clinical trials, and researches should be taken.
| S-EPMC6531224 | biostudies-literature
Project description:The treatment of acute promyelocytic leukaemia (APL) has evolved dramatically over the past several decades, making the disease a highly curable form of acute leukaemia. The discoveries of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) were landmark events, leading to historic revolutions in the treatment of APL. One major change was from chemotherapy-based to chemotherapy-free treatment regimens, and the combination of ATRA plus ATO without chemotherapy has been recommended as the standard therapy for non-high-risk APL. The other major change was from the intravenous administration of medicine in the hospital to a largely home-based oral approach, which is a more cost-effective and convenient treatment model. In this review, we focus on the evolution of therapeutic approaches for APL, as well as the challenges that remain with the current approaches.
| S-EPMC7606937 | biostudies-literature
Project description:The current treatment of patients with acute myeloid leukaemia yields poor results, with expected cure rates in the order of 30-40% depending on the biological characteristics of the leukaemic clone. Therefore, new agents and schemas are intensively studied in order to improve patients' outcomes. This review summarizes some of these new paradigms, including new questions such as which anthracycline is most effective and at what dose. High doses of daunorubicin have shown better responses in young patients and are well tolerated in elderly patients. Monoclonal antibodies are promising agents in good risk patients. Drugs blocking signalling pathways could be used in combination with chemotherapy or in maintenance with promising results. Epigenetic therapies, particularly after stem cell transplantation, are also discussed. New drugs such as clofarabine and flavopiridol are reviewed and the results of their use discussed. It is clear that many new approaches are under study and hopefully will be able to improve on the outcomes of the commonly used '7+3' regimen of an anthracycline plus cytarabine with daunorubicin, which is clearly an ineffective therapy in the majority of patients.
| S-EPMC3676948 | biostudies-other
Project description:Objective: To analyze the clinical and biological significance of the acute promyelocytic leukemia (APL) whose PML-RARa transcripts increased after induction therapy.Methods: We analyzed 9 cases of APL whose PML-RARa transcripts increased after induction treatment and compare them with APL whose PML-RARa transcripts decreased.Results: The only factor affecting increased PML-RARa transcripts was the induction protocol. The cases of increased PML-RARa transcripts received induction treatment mainly based on ATRA and ATO. The evaluation of bone marrow aspirate cytology showed that the cell percentage from myelocyte to segmented neutrophil of the patients with increased PML-RARa transcripts was significantly higher than that of the patients with decreased PML-RARa transcripts. In the follow-up, MRD in 9 cases was consistently negative.Conclusions: Our studies showed the increased PML-RARa transcripts after induction treatment had different clinical significance from the decreased PML-RARa transcripts.
| S-EPMC7877940 | biostudies-literature
Project description:BackgroundThe role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions.MethodAPL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies.FindingsAPL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner.InterpretationEndothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication.FundingNational Science Foundation of China (81670128, 81873433).
| S-EPMC7501057 | biostudies-literature
Project description:The rate of complete remission of acute promyelocytic leukemia (APL) is currently over 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). However, hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission. Neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells. We have previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin, termed ETosis/NETosis. However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown. Here, we analysed the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL. Importantly, the effect of ETs on vascular endothelium in APL was discussed. Our results showed that the ability of immature neutrophils to release ETs was impaired in APL, whereas mature neutrophils produced ETs, which were associated with activated PLTs. Moreover, ATRA+ATO induced immature neutrophil differentiation, as well as increased the release of ETs from mature neutrophils. The excessive ETs damaged endothelial cells, causing blood cell leakage. Removing ETs using DNase 1 alleviated endothelial damage and improved blood cells leakage. Our results indicate that vascular endothelial injury is at least partially associated with ETs in APL, and that targeting ETs production may be an effective approach for relieving vascular leakage and reducing the burden of bleeding in APL.
| S-EPMC9035902 | biostudies-literature
Project description:BackgroundTranscriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα.MethodsImmunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis.ResultsA PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells.ConclusionsOur results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.
| S-EPMC4453449 | biostudies-literature