Diagnosis and treatment of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL), characterized by a translocation between the promyelocytic leukemia gene (PML) on chromosome 15 and the retinoic acid receptor-α (RARα) gene on chromosome 17, has become a model for targeted treatment of cancer. Advances in our understanding of the fundamental biology of this disease have led to the development of tools for diagnosis, monitoring of minimal residual disease, and detection of early relapse. Differentiation therapy with all-trans retinoic acid in combination with chemotherapy has significantly improved survival in patients with APL. Moreover, arsenic trioxide, which induces differentiation and apoptosis of APL cells, has become standard treatment for relapsed disease, and its role in the treatment of newly diagnosed APL is under active investigation. The lessons learned from APL have broad applications to other forms of leukemia and to cancer in general, whereby molecularly targeted therapy is directed to specifically defined subgroups.     

Differentiating agents in pediatric malignancies: All-trans-retinoic acid and arsenic in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is the most potentially curable type of acute myeloid leukemia. It is characterized by the chromosomal translocation t(15;17), which results in the fusion gene PML-RAR-α. The introduction of all-trans- retinoic acid (ATRA) was a major advance in treatment of this disease. This agent induces terminal differentiation of malignant myeloid cells to mature neutrophils, and its side effects are usually well tolerated in children. ATRA does not eradicate the malignant myeloid clone in APL and, eventually, resistance develops. Arsenic trioxide induces nonterminal differentiation of malignant promyelocytes and promotes apoptosis. APL patients treated with ATRA or arsenic trioxide have rapid resolution of their coagulopathy. Because both of these drugs are well tolerated in children and their synergy has been shown in animal models, the possibility of combining ATRA and arsenic trioxide in frontline therapy for children with APL is being considered.     

PML-RARα inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by generation of the PML-RARα fusion gene. PML-RARα can homodimerize with another PML-RARα, and the hybrid binds the histone-deacetylase recruiting co-repressor complex with higher affinity than the wild-type RARα. However, the co-repressor complex is releasable by pharmacological doses of all-trans retinoic acid (ATRA). More than 90% of patients with APL achieve a complete remission (CR) with differentiation therapy consisting of ATRA combined with chemotherapy. A new synthetic retinoid, tamibaroten, showed therapeutic effectiveness in patients with ATRA-resistant APL with increased expression of cellular retinoic acid binding protein (CRABP), and about 60% of patients with relapsed APL achieved a CR. Arsenic trioxide triggers the rapid degradation of PML-RARα through the targeting of the PML moieties of the fusion protein and showed a high CR rate in relapsed APL. The combination of ATRA, chemotherapy, and/or new agents improved the long-term survival in patients with APL.     

The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells.

Acute myeloblastic leukemia (AML) may be classified in a number of ways. Using the French American British classification, the M3 form of the disease or acute promyelocytic leukemia (APL) has been found to be sensitive in vitro and in vivo to the retinoid all trans retinoic acid (ATRA). The mechanism for this is by restoration of normal gene expression through the release of histone deacetylase complexes (HDACs). In contrast to APL, other forms of AML are either nonresponsive or show blunted responses to ATRA. We evaluated if the inhibitor of HDAC activity, valproic acid (VPA), could mimic or enhance retinoid sensitivity in the AML cell line, OCI/AML-2, and clinical samples derived from patients with AML. An Affymetrix GeneChip experiment demonstrated that VPA modulated the expression of numerous genes in OCI/AML-2 cells that were not affected by ATRA including p21, a retinoid responsive gene in APL. VPA induced p21 expression in OCI/AML-2 cells and the majority of the AML samples tested; this was associated with cell cycle arrest and apoptosis not seen with ATRA alone. The addition of ATRA to VPA accentuated many of these responses, supporting the potential beneficial combination of these drugs in the treatment of AML.     

All-trans retinoic acid in the treatment of pediatric acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among ‘Nordic’ origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-α gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90–95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL.     

Acute promyelocytic leukemia current treatment algorithms

In 1957, Hillestad et al. defined acute promyelocytic leukemia (APL) for the first time in the literature as a distinct type of acute myeloid leukemia (AML) with a “rapid downhill course” characterized with a severe bleeding tendency. APL, accounting for 10–15% of the newly diagnosed AML cases, results from a balanced translocation, t(15;17) (q22;q12-21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene. The PML–RARA fusion oncoprotein induces leukemia by blocking normal myeloid differentiation. Before using anthracyclines in APL therapy in 1973, no effective treatment was available. In the mid-1980s, all-trans retinoic acid (ATRA) monotherapy was used with high response rates, but response durations were short. Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy. In this review, we summarize the evolution of APL therapy, focusing on key milestones that led to the standard-of-care APL therapy available today and discuss treatment algorithms and management tips to minimize induction mortality.Subject terms: Chemotherapy, Acute myeloid leukaemia     

Utilization of molecular phenotypes to detect relapse and optimize the management of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by a unique genetic aberration, the t(15;17) chromosome translocation. Translocation breakpoints are located within the promyelocytic leukemia (PML) locus on chromosome 15 and the retinoic acid receptor alpha (RARA) locus on chromosome 17. In the past 2 decades, critical advances have been made in understanding the molecular pathogenesis of APL. APL represents a paradigm for molecularly targeted therapy in cancer and an extraordinary model for translational research in medicine. In fact, the release of differentiation block upon treatment of APL with all-trans-retinoic acid (ATRA) has represented the first example of targeted therapy in human cancer. More recently, the advent of arsenic trioxide (ATO) has allowed further progress in the management of this disease through improved outcomes in patients receiving this agent in combination with ATRA. Finally, optimization of therapy and minimization of toxicity is feasible in this disease through careful monitoring of residual disease using polymerase chain reaction-based approaches targeting the PML-RARA fusion gene.     

Unlocking the potential of retinoic acid in anticancer therapy

All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.     

Advances in therapies for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor α (RARα) and the promyelocytic leukemia (PML) gene. The resultant PML-RARα fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 30-40%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARα fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients.     

All-trans retinoic acid and hematopoietic growth factors regulating the growth and differentiation of blast progenitors in acute promyelocytic leukemia

Although acute leukemia is generally thought to be characterized by maturation arrest, it has been shown that differentiation occurs in blast cells of acute myelogenous leukemia (AML) in vitro as well as in vivo, and that morphologically abnormal mature polymorphonuclear neutrophils (PMNs) often seen in patients with AML are possibly derived from spontaneously differentiating leukemic cells. Acute promyelocytic leukemia (APL) is an unique example in which these features of AML are evident in an almost complete form; administration of all-trans retinoic acid (ATRA) induces differentiation of neoplastic cells into mature neutrophils and successfully induce complete remission in most patients. However, PMNs appearing during ATRA treatment are morphologically abnormal, as indicated not only by the presence of Auer rods but also by neutrophil secondary-granule deficiency that is commonly seen in AML. Moreover, ATRA has heterogeneous effects on the growth of blast progenitors in APL in different patients, being inhibitory, stimulatory or ineffective, which might account in part for the leukemia relapse in patients treated with ATRA alone. Hematopoietic growth factors regulate the growth of blast progenitors in APL. Among them, granulocyte colony-stimulating factor (G-CSF) is unique in that it preferentially stimulates clonal growth, but not self-renewal, in many APL cases, and synergistically enhances the differentiation-inducing effect of ATRA when used in combination. Many other compounds also exert such synergistic effects with ATRA, for which a variety of mechanisms have been suggested. It is crucial to precisely elucidate the functions of these molecules governing the growth/differentiation balance of AML blast progenitors and the mechanisms underlying their deregulated differentiation program in order to achieve effective differentiation therapy for patients with AML, not restricted to APL.     

Acute promyelocytic leukemia: where did we start,where are we now,and the future

Historically, acute promyelocytic leukemia (APL) was considered to be one of the most fatal forms of acute leukemia with poor outcomes before the introduction of the vitamin A derivative all-trans retinoic acid (ATRA). With considerable advances in therapy, including the introduction of ATRA initially as a single agent and then in combination with anthracyclines, and more recently by development of arsenic trioxide (ATO)-containing regimens, APL is now characterized by complete remission rates of 90% and cure rates of ∼80%, even higher among low-risk patients. Furthermore, with ATRA–ATO combinations, chemotherapy may safely be omitted in low-risk patients. The disease is now considered to be the most curable subtype of acute myeloid leukemia (AML) in adults. Nevertheless, APL remains associated with a significant incidence of early death related to the characteristic bleeding diathesis. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure.     

Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical results and open questions

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia. The specific translocation t(15;17), which results in the fusion gene PML–RARA is the diagnostic and pathomechanistic hallmark of APL. By combination, treatment consisting of the differentiating agent all-trans retinoic acid (ATRA), which targets this molecular lesion, and cytotoxic chemotherapy, cure can be achieved in over 70% of patients. Recently, arsenic trioxide (ATO) has emerged to be the most active single agent in the treatment of APL. Previous studies employing ATO in relapse settings reported average complete remission rates of 85% and a mean overall survival of over 60%. In recent approaches installing ATO in first-line treatment, ATO-induced response rates comparable to previous combination regimen. The results of these newer studies indicate that the backbone of chemotherapy can be dramatically reduced or completely replaced by ATO and ATRA with similar or even better outcome.     

早幼粒白血病-维甲酸受体α融合蛋白对RIAM基因转录的负调控作用探讨

目的:研究异常转录因子早幼粒白血病-维甲酸受体α(promyelocytic leukemia-retinoic acid receptor alpha,PML-RARα)融合蛋白对RIAM基因的转录调控机制.方法:利用表达谱数据库(GSE1159)比较RIAM基因在急性髓系白血病(acute myeloid leukemia,AML)各亚型中的表达情况,以及RIAM基因和PML-RARα融合蛋白之间的相关性.采用蛋白质印迹法和实时荧光定量-PCR法分别检测PML-RARα融合蛋白和RIAM基因在急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)模式细胞株PR9及APL患者来源的细胞株NB4中的表达情况,以及在全反式维甲酸(all-trans retinoic acid,ATRA)处理前后的RIAM mRNA的表达情况.利用染色质免疫沉淀技术检测细胞内PML-RARα融合蛋白在RIAM基因启动子附近的结合情况.结果:RIAM基因在APL(即M3型AML)中的表达水平明显低于其他AML亚型(M0、M1、M2、M4、M5和M7型)和正常造血细胞(P＜0.05).随着PML-RARα融合蛋白的表达,RIAM基因的表达水平明显降低.ATRA能激活RIAM基因的表达,且PML-RARα融合蛋白的表达能增强ATRA对RIAM基因表达的激活效应.PML-RARα融合蛋白结合在RIAM基因的启动子区域.结论:RIAM基因是PML-RARα融合蛋白的靶基因,PML-RARα融合蛋白通过结合到RIAM基因的启动子区域对其转录进行负调控.     

治疗急性早幼粒细胞白血病的几个问题

 急性早幼粒细胞白血病（APL）为急性髓系白血病的一个亚型,以进展快,易发生弥散性血管内凝血（DIC）和死亡率高为特征。95 %以上APL患者有典型染色体易位t（15;17）形成PML-RARα融合基因。1986年以来,中国首创以全反式维甲酸（ATRA）和亚砷酸（ATO）治疗APL,使APL的转归大大改观,成为仅用药物可治愈的AML。结合作者经验讨论治疗APL中的有关问题。     

Translocations of the RARalpha gene in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) has been recognized as a distinct clinical entity for over 40 years. Although relatively rare among hematopoietic malignancies (approximately 10% of AML cases), this disease has attracted a particularly good share of attention by becoming the first human cancer in which all-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, was able to induce complete remission (CR). ATRA induced remission is not associated with rapid cell death, as in the case of conventional chemotherapy, but with a restoration of the 'normal' granulocytic differentiation pathway. With this remarkable medical success story APL has overnight become a paradigm for the differentiation therapy of cancer. A few years later, excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease, the t(15:17) reciprocal chromosomal translocation, involves a fusion between the retinoic acid receptor alpha (RARalpha) gene and a previously unknown locus named promyelocytic leukemia (PML). Consequence of this gene rearrangement is expression of the PML-RARalpha chimeric oncoprotein, which is responsible for the cellular transformation as well as ATRA response that is observed in APL. Since this initial discovery, a number of different translocation partner genes of RARalpha have been reported in rarer cases of APL, strongly suggesting that disruption of RARalpha underlies its pathogenesis. This article reviews various rearrangements of the RARalpha gene that have so far been described in literature, functions of the proteins encoded by the different RARalpha partner loci, and implications that these may have for the molecular pathogenesis of APL.     

Cotylenin A--a plant growth regulator as a differentiation-inducing agent against myeloid leukemia

Acute myeloid leukemia (AML) is characterized by the arrest of differentiation leading to the accumulation of immature cells. This maturation arrest can be reversed by certain agents. Although differentiation therapy for patients with acute promyelocytic leukemia (APL) using all-trans retinoic acid (ATRA) has been established, the clinical response of AML patients other than those with APL to ATRA is limited. We must consider novel therapeutic drugs against other forms of AML for the development of a differentiation therapy for leukemia. Regulators that play an important role in the differentiation and development of plants or invertebrates may also affect the differentiation of human leukemia cells through a common signal transduction system, and might be clinically useful for treating AML. Cotylenin A, a plant growth regulator, is a potent and novel inducer of the monocytic differentiation of human myeloid leukemia cell lines and leukemia cells freshly isolated from AML patients.     

Management of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) has become the most potentially curable subtype of acute myeloid leukemia (AML) in adults. With current treatment strategies that incorporate all-trans retinoic acid (ATRA), long-term disease-free survival and potential cure rates of 70% to 80% can be expected. Such progress reflects what can be accomplished with insights into the molecular pathogenesis of leukemia, identification of a molecular target, and rapid accrual to a series of clinical trials. The leukemic promyelocytes from patients with APL are uniquely susceptible to a variety of novel agents in addition to ATRA, including arsenic trioxide, and in preliminary studies, gemtuzumab ozogamicin, the immunoconjugate comprised of an anti-CD33 monoclonal antibody linked to the potent cytotoxic agent calicheamicin. Incorporation of such agents into the treatment of patients with high-risk disease may be an important future direction to pursue.     

Acute Myelogenous Leukemia without Maturation with a Retinoic Alpha-Receptor Deletion: A Case Report

Acute promyelocytic leukemia (APL) is characterized by a t(15;17) which fuses the 17q retinoic acid alpha-receptor sequence to the 15q PML gene sequence. The resulting fusion product plays a role in the development and maintenance of APL, and is very rarely found in other acute myeloid leukemia (AML) subtypes. Rare complex APL genomic rearrangements have retinoic acid alpha-receptor sequence deletions. Here we report a retinoic acid alpha-receptor sequence deletion in a case of AML without differentiation. To our knowledge, this is the first example of a retinoic acid alpha-receptor sequence deletion in this AML subtype.Key words: Acute myelogenous leukemia without maturation, PML/RAR?, Deletion, t(15;17)(q22;q21), Acute promyelocytic leukemia, AML-M3, AML-M1