The potential for antitumor vaccination in acute myelogenous leukemia

 While many advances have been made in the treatment of patients with cancer, significant challenges that remain include tumor cell resistance and the toxicity associated with currently used intensive chemotherapeutic regimens. This is particularly true for patients with acute myelogenous leukemia (AML). Most patients with AML usually are able to achieve complete remission, but only a minority obtain long-term survival. In addition, much of the success achieved has been due to escalation of chemotherapeutic dosing and hematopoietic stem cell transplantation. There is thus a great need for improved therapies which would ideally be able to circumvent drug resistance and more specifically target leukemic cells. Advances in immunobiology over the past century have led to new hope for the development of immune-mediated vaccine therapies for patients with cancer. This review focuses on the development of vaccine approaches for treatment of AML and some of the potential advantages and problems. Received: 10 December 1996 / Accepted: 12 May 1997     

Genetic and epigenetic insights into uveal melanoma

Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to exam the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. In this context, there has been tremendous progress in the field of UM pathogenesis. Herein, we review the literature with emphasis on genetic alterations, epigenetic modifications and signaling pathways as well as possible biomarkers in UM. In addition, different research models for UM are discussed. New insights and major challenges are outlined in order to evaluate the current status for this potentially devastating disease.     

New avenues for genetics guided therapeutic approaches in AML

The development of single nucleotide polymorphism (SNP) microarray analysis and next generation sequencing (NGS) has significantly contributed to comprehensively characterize the genetic changes underlying acute myeloid leukemia (AML). These genomics technologies have led to the identification of an increasing number of genomic aberrations and gene mutations that cause epigenetic changes and lead to deregulated gene expression. In accordance, AML patients present with a distinct and almost individual combination of somatically acquired genetic alterations reflecting the molecular heterogeneity of the disease. Some of these are known driver mutations perturbing self-renewal, proliferation, and hematopoietic differentiation, whereas many mutations also represent mere passenger events, which do not significantly contribute to AML. In the future, we will have to discriminate driver from passenger mutations and in addition it will be crucial to evaluate the prognostic and predictive values of the respective driver mutations, especially in the context of the overall genetic background. While first genetic markers have already been translated into the daily clinical routine by impacting treatment decisions, novel biomarkers are needed especially to improve the effectiveness of molecular targeted therapies, which have to be put into the perspective of mutational networks to further “precision medicine” by personalized combination treatment approaches.     

Clonal hematopoiesis and preleukemia—Genetics,biology, and clinical implications

Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease‐specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH‐related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non‐hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.     

Recent Advances in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Allogeneic hematopoietic stem cell transplantation remains an important treatment modality for patients with acute myeloid leukemia (AML). Recent advances have extended donor availability for patients without matched donors. Transplantation is now increasingly offered to older patients, including those above 70 years and less fit individuals. Better prognostic models are being developed. Proceeding faster to transplantation with haploidentical donors if an urgent transplant is needed, such as in patients with detectable minimal residual disease, may allow more patients to get to transplant, and it is hoped more will be cured from their disease. With continuous improvements in treatment-related toxicity and mortality, relapse has become the most important cause of treatment failure, and novel approaches are needed to make the next big leap in the treatment of this disease with transplantation. In this review we aim to summarize recent advances and provide future research directions in the transplantation for patients with AML.     

Znaczenie mutacji genów modulujących zmiany epigenetyczne w ostrej białaczce szpikowej

The epigenetic regulation is a complex process that affects the gene expression. Recent studies revealed abberant DNA methylation patterns in acute myeloid leukemia (AML) patients suggesting the significant role of these alterations in leukemogenesis. Additionally, the next generation sequencing (NGS) technology uncover mutations of IDH1/2, TET2, DNMT3A and EZH2 genes involved in DNA methylation processes or post translational histone modifications. Although, the functional application and precise mechanism in which the mutations contribute to impaired haematopoesis remain elusive, emerging evidences indicate the complexity of epigenetic deregulation processes which cooperate with AML recurrent mutations leading to malignant transformation.     

Genetic and epigenetic alterations during renal carcinogenesis

Renal cell carcinoma (RCC) is not a single entity, but comprises a group of tumors including clear cell RCC, papillary RCC and chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more clinicopathologically aggressive clear cell RCC may develop. Since renal carcinogenesis is associated with neither chronic inflammation nor persistent viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal tumors, precancerous conditions in the kidney have been rarely described. However, regional DNA hypermethylation on C-type CpG islands has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in precancerous conditions are basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant cancers, and even determine patient outcome. The list of tumor-related genes silenced by DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and therapy of RCCs.     

Hematopoietic Stem Cell Transplantation in Adults with Acute Myeloid Leukemia

Hematopoietic stem cell transplantation (HSCT) is an integral part of the treatment of many patients with acute myeloid leukemia (AML). Despite extensive study, the appropriate role and timing of allogeneic and autologous transplantation in AML are poorly defined. This review critically analyzes the extensive literature, focusing on the recent advances, and provides practical recommendations for the use of HSCT in AML.     

Mutations of GATA1, FLT3, MLL-partial tandem duplication, NRAS, and RUNX1 genes are not found in a 7-year-old Down syndrome patient with acute myeloid leukemia (FAB-M2) having a good prognosis

The prognosis of leukemia developed in Down syndrome (DS) patients has improved markedly. Most DS leukemia occurs before 3 years of age and is classified as acute megakaryocytic leukemia (AMKL). Mutations in the GATA1 gene have been found in almost all DS patients with AMKL. In contrast, it has been shown that occurrence of DS acute myeloid leukemia (DS-AML) after 3 years of age may indicate a higher risk for a poor prognosis, but its frequency is very low. Age is one of the significant prognostic indicators in DS-AML. The prognostic factor of gene alterations has not been reported in older DS-AML patients. We here describe the case of a 7-year-old DS boy with AML-M2, who had no history of transient abnormal myelopoiesis or any clinical poor prognostic factors, such as high white blood cell counts or extramedullary infiltration. We molecularly analyzed the GATA1, FLT3, MLL-partial tandem duplication, NRAS, and RUNX1 (previously AML1) genes and did not detect any alterations. The patient has lived for more than 5 years after treatment on the AML99-Down protocol in Japan. This suggests that a patient lacking these genes alterations might belong to a subgroup of older DS-AML patients with good prognosis. Accumulation of more data on older pediatric DS-AML patients is needed.     

Epigenetic regulation in cell senescence

Cell senescence, which is an irreversible state of cell proliferative arrest, has emerged as a potentially important contributor to tissue dysfunction and organismal ageing. Cell senescence is triggered by a variety of senescence stressors, which affect gene expression and multiple signalling pathways that give rise to various senescence phenotypes. Epigenetic mechanisms, as critical regulators of chromosomal architecture and gene expression, have added an extra dimension to the molecular mechanisms of cell senescence. Cell senescence is accompanied by changes in DNA methylation, histone-associated epigenetic processes, chromatin remodelling and ncRNA expression. Those senescence-associated epigenetic alterations interact with the senescence regulatory programme networks and lead to various cell senescence phenotypes. This review provides a comprehensive overview of epigenetic changes and their effects on cell senescence. The differences in epigenetic alterations among different types of senescence are also discussed. Furthermore, we summarise the interactions among different epigenetic mechanisms during cell senescence and analyse the possibility of using epigenetic signatures as biomarkers and therapeutic targets for the treatment of senescence-associated diseases.     

Epigenetic modifications induced by Helicobacter pylori infection through a direct microbe–gastric epithelial cells cross-talk

One of the most fascinating aspects of the field of epigenetics is the emerging ability of environmental factors to trigger epigenetic changes in eukaryotic cells, thus contributing to transient or stable, and potentially heritable, changes in gene expression program in the absence of alteration in DNA sequence. Epigenetic response may result in cell adaptation to environmental stimuli or, in some instances, may contribute to generation or progression of different kind of diseases. A paradigmatic case of disease that is accompanied by multiple epigenetic alterations is gastric cancer, among other relevant examples. In turn, Helicobacter pylori (Hp) infection has been associated as a leading cause of gastric cancer. One possible hypothesis is that Hp–gastric cell interaction initiates an epigenetic reprogramming of host cell genome that may favor tumorigenesis. Accordingly, an abundance of experimental evidence indicates that several epigenetic alterations underlie the gastric cancerogenesis process and that these alterations represent one of the major hallmarks of gastric cancer. However, several critical questions remain unanswered: Does Hp directly provoke epigenetic alterations? Which mechanisms underlie these phenomena? Based on currently available data, it is often arduous to discriminate between the epigenetic modifications directly triggered by Hp–gastric cell interaction and those alterations that are mediated by inflammation process or by many other molecular and genetic events occurring during the gastric cancer progression. We will review our present knowledge of epigenetic modifications and alterations proven to occur in host cells as a direct consequence of Hp infection.     

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

Based on the individual genetic profile, acute myeloid leukemia (AML) patients are classified into clinically meaningful molecular subtypes. However, the mutational profile within these groups is highly heterogeneous and multiple AML subclones may exist in a single patient in parallel. Distinct alterations of single cells may be key factors in providing the fitness to survive in this highly competitive environment. Although the majority of AML patients initially respond to induction chemotherapy and achieve a complete remission, most patients will eventually relapse. These points toward an evolutionary process transforming treatment‐sensitive cells into treatment‐resistant cells. As described by Charles Darwin, evolution by natural selection is the selection of individuals that are optimally adapted to their environment, based on the random acquisition of heritable changes. By changing their mutational profile, AML cell populations are able to adapt to the new environment defined by chemotherapy treatment, ultimately leading to cell survival and regrowth. In this review, we will summarize the current knowledge about clonal evolution in AML, describe different models of clonal evolution, and provide the methodological background that allows the detection of clonal evolution in individual AML patients. During the last years, numerous studies have focused on delineating the molecular patterns that are associated with AML relapse, each focusing on a particular genetic subgroup of AML. Finally, we will review the results of these studies in the light of Darwinian evolution and discuss open questions regarding the molecular background of relapse development.     

Hepatitis C virus and hepatocarcinogenesis

Hepatitis C virus (HCV) is an RNA virus that is unable to integrate into the host genome. However, its proteins interact with various host proteins and induce host responses. The oncogenic process of HCV infection is slow and insidious and probably requires multiple steps of genetic and epigenetic alterations, the activation of cellular oncogenes, the inactivation of tumor suppressor genes, and dysregulation of multiple signal transduction pathways. Stellate cells may transdifferentiate into progenitor cells and possibly be linked to the development of hepatocellular carcinoma (HCC). Viral proteins also have been implicated in several cellular signal transduction pathways that affect cell survival, proliferation, migration and transformation. Current advances in gene expression profile and selective messenger RNA analysis have improved approach to the pathogenesis of HCC. The heterogeneity of genetic events observed in HCV-related HCCs has suggested that complex mechanisms underlie malignant transformation induced by HCV infection. Considering the complexity and heterogeneity of HCCs of both etiological and genetic aspects, further molecular classification is required and an understanding of these molecular complexities may provide the opportunity for effective chemoprevention and personalized therapy for HCV-related HCC patients in the future. In this review, we summarize the current knowledge of the mechanisms of hepatocarcinogenesis induced by HCV infection.