Epidemiology of childhood leukemia in the presence and absence of Down syndrome

Down syndrome (DS) is a common congenital anomaly, and children with DS have a substantially higher risk of leukemia. Although understanding of genetic and epigenetic changes of childhood leukemia has improved, the causes of childhood leukemia and the potential role of environmental exposures in leukemogenesis remain largely unknown. Although many epidemiologic studies have examined a variety of environmental exposures, ionizing radiation remains the only generally accepted environmental risk factor for childhood leukemia. Among suspected risk factors, infections, exposure to pesticides, and extremely low frequency magnetic fields are notable. While there are well-defined differences between leukemia in children with and without DS, studies of risk factors for leukemia among DS children are generally consistent with trends seen among non-DS (NDS) children.We provide background on DS epidemiology and review the similarities and differences in biological and epidemiologic features of leukemia in children with and without DS. We propose that both acute lymphoblastic and acute myeloblastic leukemia among DS children can serve as an informative model for development of childhood leukemia. Further, the high rates of leukemia among DS children make it possible to study this disease using a cohort approach, a powerful method that is unfeasible in the general population due to the rarity of childhood leukemia.     

The Philadelphia chromosome in acute leukemia.

The cytogenetics, cytology and cytochemistry, clinical findings, therapeutic response and survival of patients presenting with acute leukemia and the Philadelphia chromosome (Ph1) are briefly reviewed based upon a survey of the world literature and 16 cases seen at the University of Minnesota during the last 10 years. Details regarding the 16 cases from the University of Minnesota series are presented and two appendices listing the majority of reports of Ph1 + acute leukemia are included. Comparison of adults with Ph1+ and Ph1- acute leukemia demonstrate important clinical, therapeutic and prognostic differences. In general, patients with Ph1+ acute leukemia respond less well to treatment and survive significantly shorter periods of time. Since the presence of the Philadelphia chromosome in acute leukemia has therapeutic and prognostic significance, marrow chromosome studies should be performed in adults presenting with acute leukemia, especially acute lymphocytic leukemia.     

Development of a multi-step leukemogenesis model of MLL-rearranged leukemia using humanized mice

Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ(-/-) (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia.     

MicroRNAs and response to therapy in leukemia

A variety of epigenetic factors involved in leukemia pathogenesis. Among various epigenetic factors, microRNAs (miRNAs) have emerged as important players, which affect a sequence of cellular and molecular signaling pathways. Leukemia is known as progressive cancer, which is related to many health problems in the world. It has been shown that the destruction of the blood-forming organs could lead to abnormal effects on the proliferation and development of leukocytes and their precursors. Despite many attempts for approved effective and powerful therapies for patients with leukemia, finding and developing new therapeutic approaches are required. One of the important aspects of leukemia therapy, identification of underlying cellular and molecular mechanisms involved in the pathogenesis of leukemia. Several miRNAs (ie, miR-103, miR-101, mit-7, let-7i, miR-424, miR-27a, and miR-29c) and play major roles in response to therapy in patients with leukemia. miRNAs exert their effects by targeting a variety of targets, which are associated with response to therapy in patients with leukemia. It seems that more understanding about the roles of miRNAs in response to therapy in patients with leukemia could contribute to better treatment of patients with leukemia. Here, for the first time, we summarized various miRNAs, which are involved in response to therapy in the treatment patients with leukemia.     

MicroRNA in leukemia: Tumor suppressors and oncogenes with prognostic potential

Leukemia is known as a progressive malignant disease, which destroys the blood-forming organs and results in adverse effects on the proliferation and development of leukocytes and their precursors in the blood and bone marrow. There are four main classes of leukemia including acute leukemia, chronic leukemia, myelogenous leukemia, and lymphocytic leukemia. Given that a variety of internal and external factors could be associated with the initiation and progression of different types of leukemia. One of the important factors is epigenetic regulators such as microRNAs (miRNAs) and long noncoding RNAs (ncRNA). MiRNAs are short ncRNAs which act as tumor suppressor (i.e., miR-15, miR-16, let-7, and miR-127) or oncogene (i.e., miR-155, miR-17-92, miR-21, miR-125b, miR-93, miR-143-p3, miR-196b, and miR-223) in leukemia. It has been shown that deregulation of these molecules are associated with the initiation and progression of leukemia. Hence, miRNAs could be used as potential therapeutic candidates in the treatment of patients with leukemia. Moreover, increasing evidence revealed that miRNAs could be used as diagnostic and prognostic biomarkers in monitoring patients in early stages of disease or after received chemotherapy regimen. It seems that identification and development of new miRNAs could pave to the way to the development new therapeutic platforms for patients with leukemia. Here, we summarized various miRNAs as tumor suppressor and oncogene which could be introduced as therapeutic targets in treatment of leukemia.     

A Statistical Survey of Leukemia in Ontario and at the Ontario Cancer Foundation Clinics, 1938-1958

In Ontario, leukemia causes about 4% of all cancer deaths, ranging from nearly 50% at under 5 years of age to 1-3% at age 50 and over. Age-specific death rates are highest among older people; at all ages, male deaths exceed female deaths. Only about 20% of all leukemia patients in Ontario are registered at Ontario Cancer Clinics; the proportion changed sharply with the advent of chemotherapy. For 1258 patients registered in 1938-1963, the crude one-year survival rate was 50%, ranging from 9% for acute leukemia to about 60% for non-acute lymphatic and myeloid leukemia. The long-term outlook was much better for non-acute lymphatic leukemia than for non-acute myeloid leukemia. For acute leukemia, the treatment of choice was chemotherapy; for non-acute lymphatic leukemia, radiotherapy was used, followed, if required, by chemotherapy or further radiotherapy. For non-acute myeloid leukemia, the advantage of chemotherapy over radiotherapy was not established.     

An Immunocompetent Mouse Model for MLL/AF9 Leukemia Reveals the Potential of Spontaneous Cytotoxic T-Cell Response to an Antigen Expressed in Leukemia Cells

Leukemia differs substantially with respect to stromal milieu from tumors that progress locally as solid masses, and the physiological importance of immunosurveillance in leukemia remains unclear. However, currently available mouse leukemia models have critical limitations in the context of analyzing immunological regulation of leukemia development. In this study, we transferred mouse MLL/AF9 leukemia-initiating cells into immunocompetent recipient mice without any pre-conditioning such as irradiation, and then analyzed the spontaneous T cell response to an immunogenic antigen expressed in leukemia cells. When the minimum numbers of leukemia-initiating cells for engraftment were transferred, leukemia cells were eradicated by the adaptive immune response in most, if not all, wild-type mice, but not in Rag2 ^-/- recipient mice, which lack adaptive immunity. By contrast, mice transplanted with larger numbers of leukemia cells always developed leukemia. In mice with advanced leukemia, antigen-specific CTLs were also expanded, but were unresponsive to antigen stimulation and expressed high levels of PD-1 and LAG-3. These results provide the first clear demonstration that the spontaneous CTL response to a tumor-cell antigen has the potential to eradicate leukemia, whereas antigen-specific CTLs are exhausted in animals with advanced leukemia. This immunocompetent mouse leukemia model provides a useful platform for developing effective immunotherapies against leukemia.     

Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism

In acute myeloid leukemia (AML), the chances of achieving disease-free survival are low. Studies have demonstrated a supportive role of endothelial cells (ECs) in normal hematopoiesis. Here we show that similar intercellular relationships exist in leukemia. We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. In this inflammatory state, activated ECs induce the adhesion of a sub-set of leukemia cells through the cell adhesion molecule E-selectin. These adherent leukemia cells are sequestered in a quiescent state and are unaffected by chemotherapy. The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. Interestingly, differing leukemia subtypes modulate this process to varying degrees, which may explain the varied response of AML patients to chemotherapy and relapse rates. Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. Together, the data defines a new mechanism describing how ECs and leukemia cells interact during leukemogenesis, which could be used to develop novel treatments for those with AML.     

A positive difference in nature of envelopes of thymus- and uterus-derived leukemia viruses of AKR mice.

Thymus-derived leukemia virus of AKR/J mice was inactivated by anti-theta antiserum. But it was not inactiviated by the antiserum which had been absorbed with intact thymus cells of AKR/J or RF/J mice, and by anti-uterus-derived leukemia virus antiserum. In contrast, uterus-derived leukemia virus of the strain was not inactivated by anti-theta antiserum, but was neutralized by anti-uterus-derived leukemia virus antiserum. The results suggest the possibility that some constitutents of the envelope of thymus-derived leukemia virus are derived from the plasma membrane of thymus cells of AKR mice at the time of budding and that such constituents are not associated with the enveloped of uterus-derived leukemia virus.     

NEWER THERAPY FOR LEUKEMIA,POLYCYTHEMIA, AND LYMPHOMA

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin''s disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.     

The 1952 outbreak of encephalitis in California; vector control aspects

X-radiation remains the treatment of choice in most cases of leukemia and lymphoma, but new agents are playing an increasing role in therapy. Radioactive phosphorus does not produce radiation sickness and results with it are comparable to those of x-ray therapy in chronic leukemia. Urethane and nitrogen mustard may produce remissions in patients with chronic leukemia who have become resistant to radiation. Triethylene melamine may be administered orally with nitrogen mustard-like effects and is undergoing further trial. Aminopterin, ACTH and cortisone often cause short remissions in acute leukemia. Urethane is the best treatment available for multiple myeloma. Polycythemia vera is well controlled by radioactive phosphorus combined with venesection. Nitrogen mustard is often effective and triethylene melamine shows promise in Hodgkin's disease. Antianemic substances such as iron and liver extract are of no value in the treatment of anemia caused by leukemia, lymphoma and myeloma.     

Recognition of leukemia in skeletal remains: Report and comparison of two cases

Recognition of disease in the archeologic record is facilitated by characterization of the skeletal impact of documented (in life) disease. The present study describes the osteological manifestations of leukemia as identified in the skeletons of two individuals diagnosed during life: a 3-year-old black girl with acute lymphocytic leukemia and a 60-year-old white male with acute myelogenous leukemia in the Hamann-Todd collection. Contrasting with the lack of specificity of radiologic findings, macroscopic skeletal changes appear sufficiently specific to allow distinguishing leukemia from other forms of cancer. While leukemia appears confidently diagnosable, distinguishing among the varieties (e.g., myelogenous and lymphocytic) does not appear possible at this time. Skeletal findings in leukemia are presented in tabular form to facilitate their application to future diagnosis of the disease in the archaelogical record. Am J Phys Anthropol 102:481–496, 1997. © 1997 Wiley-Liss, Inc.     

Cytogenetic and molecular studies of Down syndrome individuals with leukemia.

There is an increased risk of leukemia in Down syndrome (DS) patients, with estimates ranging from 14 to 30 times the incidence rate observed for chromosomally normal children. Furthermore, one type of leukemia, called "transient leukemia" (TL), occurs almost exclusively in DS infants. The basis of the association between DS and leukemia is unknown, but we and others have hypothesized that it may be influenced by the mechanism of origin of the extra chromosome. Therefore, we initiated a cytogenetic and molecular study of nondisjunction in leukemia DS individuals. To date, we have obtained blood and/or tissue samples from 55 individuals consisting of 17 cases with TL, 7 cases of acute nonlymphocytic leukemia subtype M7 (ANLL-M7, or acute megakaryoblastic leukemia, postulated to be related to TL), and 31 cases of other forms of leukemia. Analysis of these cases suggests differences between DS children with TL and those with other types of leukemia or DS individuals with no history of leukemia. Specifically, the TL and ANLL-M7 cases have a highly significant increase in the frequency of "atypical" constitutional karyotypes (i.e., mosaic trisomies, rings, and/or isochromosomes) and are almost always male. Additionally, genetic mapping studies suggest an increase in the frequency of disomic homozygosity, especially in proximal 21q, in DS individuals with TL and ANLL-M7.     

Electron microscopy: a contribution to further classification of acute unclassifiable childhood leukemia

The ultrastructural, light microscopical and immunological features of twelve cases of acute childhood leukemia are described. Nine cases were unclassifiable by light microscopy, morphology and cytochemistry, and three were difficult to classify because of a low percentage of Sudan-Black B positive blasts. By means of electron microscopy (including peroxidase cytochemistry), two main groups were seen: 1. Acute myeloid leukemia, in which could be distinguished a) a more differentiated myeloid leukemia, b) a leukemia with megakaryoblastic involvement and c) a minimally differentiated acute myeloid leukemia with granules present and 2. lymphoblastic leukemia. One case could not be classified. The first group included two possible cases of a hybrid leukemia with CD19 or CD10 positivity as well as ultrastructural peroxidase activity. We conclude that electron microscopy aids to further classification of minimally differentiated and hybrid acute leukemias.     

A hypothesis: radiation-related leukemia is mainly attributable to the small number of people who carry pre-existing clonally expanded preleukemic cells

Human leukemia frequently involves recurrent translocations. Since radiation is a well-known inducer of both leukemia and chromosomal translocations, it has long been suspected that radiation might cause leukemia by inducing specific translocations. However, recent studies clearly indicate that spontaneous translocations specific to acute lymphocytic leukemia (ALL) actually occur much more frequently than do leukemia cases with the same translocations. Moreover, the ALL-associated translocation-bearing cells are often found to have clonally expanded in individuals who do not develop ALL. Since radiation-induced DNA damage is generated essentially randomly in the genome, it does not seem likely that radiation could ever be responsible for the induction of identical translocations of relevance to ALL in multiple cells of an individual and hence be the primary cause of radiation-related leukemia. An alternative hypothesis described here is that the radiation-related ALL risk for a population is almost entirely attributable to a small number of predisposed individuals in whom relatively large numbers of translocation-carrying pre-ALL cells have accumulated. This preleukemic clone hypothesis explains various known characteristics of radiation-related ALL and implies that people who do not have substantial numbers of preleukemic cells (i.e. the great majority) are likely at low risk of developing leukemia. The hypothesis can also be applied to chronic myelogenous leukemia and to young-at-exposure cases of acute myelogenous leukemia.     

Disturbances of coagulation and fibrinolysis in patients with acute leukemia]

In 30 patients with acute leukemia--18 with myeloblastic acute leukemia, 1 with promyelocytic acute leukemia, 4 with myelo-monocytic acute leukemia, 4 with chronic myelocytic leukemia exacerbation--coagulation and fibrinolysis tests were performed in different stage of the disease. Most of the disorders were noted in the III period of the disease (significant levels of the factors II, IX decrease, clot contractility weakness and platelets count decrease). I in patients with manifestation of haemorrhagic diathesis and in patients without them disturbances in examined tests were similar, but platelets count in patients with bleeding was always significantly reduced. The main reasons of the bleeding in acute leukemias are thrombocytopenia together with the in coagulation factors.     

Case report of isochromosome 17q in acute myeloid leukemia with myelodysplasia-related changes after treatment with a hypomethylating agent

Isochromosome 17q is a relatively common karyotypic abnormality in medulloblastoma, gastric, bladder, and breast cancers. In myeloid disorders, it is observed during disease progression and evolution to acute myeloid leukemia in Philadelphia-positive chronic myeloid leukemia. It has been reported in rare cases of myelodysplastic syndrome, with an incidence of 0.4-1.57%. Two new agents have been approved for treatment of myelodysplastic syndrome/chronic myelomonocytic leukemia. These are the hypomethylating agents, 5-azacytidine and decitabine, recommended by consensus guidelines for high-risk myelodysplastic syndrome patients not eligible for hematopoietic stem cell transplantation. We present a case of chronic myelomonocytic leukemia with normal cytogenetics at diagnosis treated with decitabine (with good response); however, the patient evolved to acute myeloid leukemia with i(17q) shortly after suspending treatment. To the best of our knowledge, this is the first report of acute myeloid leukemia with myelodysplasia-related changes with i(17q) after the use of a hypomethylating agent.     

Platelet Changes in Acute Leukemia

Acute leukemia is a hematopoietic stem cell malignant disease, with abnormal proliferation of leukemic and immature cells that suppress the production of normal blood cells and extensively invade peripheral tissues. The bleeding complications are very common in acute leukemia and often lead to death. One major cause for hemorrhage is thrombocytopenia, which is caused by the replacement of normal bone marrow cells with leukemic cells and the inhibition of megakaryocytes functions. Declines in platelet count as well as in function in acute leukemia have been reported in many studies. Here, we reviewed the literatures concerning platelet changes in acute leukemia.     

Differences in pathogenicity among cloned sublines of a murine leukemia virus.

Five clones of the lymphatic leukemia virus 334C were isolated by a procedure designed to maintain homogeneity of the clones. Three of these induced leukemia in mice with the time course of the uncloned parental virus, one induced leukemia with a delayed time course, and one seemed to be biologically inactive. When the clone inducing leukemia most rapidly and the clone inducing leukemia least rapidly were subcloned, the subclones retained the leukemogenicity of the parental clones. The electrophoretic patterns of purified virion proteins and hybridization of viral RNAs with virus-specific DNA suggest that these clones are two closely related variants, not unrelated viruses. Furthermore, in mice infected with these two clones, viral RNA appears in thymuses and spleens at the same time after infection and at nearly the same concentrations. Thus, variations in leukemogenicity can be determined by a genetic property of an ecotropic leukemia virus, and this property is expressed in some manner more subtle than simple control of replication.     

外泌体在白血病中的重要调控作用

目前,白血病复发是患者死亡的主要原因之一。肿瘤细胞和微环境的相互作用,以及隐匿在骨髓中的肿瘤干细胞,促进了白血病的复发和向淋巴组织的转移,因此白血病的治疗、转移和复发问题受到广泛关注。外泌体是由绝大多数细胞分泌的双层脂质膜囊泡,可以调控细胞间的交流和信息传递。在白血病细胞、基质细胞和内皮细胞之间的相互联系中都涉及到外泌体,白血病细胞来源的外泌体存在于白血病患者的血浆中,能把其携带的白血病相关抗原及微小RNA呈递给靶细胞,促进白血病肿瘤细胞的增殖,有助于肿瘤细胞实现免疫逃避,保护白血病细胞抵抗化疗药物导致的细胞毒性作用,促进血管生成及肿瘤细胞的迁移。因此,外泌体与白血病的转移、治疗及预后密切相关,可以用来检测和监测白血病的进展。本文综述了外泌体的来源、形成与分泌机制,以及外泌体在白血病发生前、发展中、预后和免疫治疗中所扮演的重要角色。