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.     

地西他滨单药及联合半程和全程HA方案治疗骨髓增生异常综合征和急性髓系白血病的效果

目的:研究骨髓增生异常综合征和急性髓系白血病治疗中地西他滨单药及联合半程和全程HA方案的效果。方法:采用回顾性分析方法,选择2016年6月至2019年6月入院的80例骨髓增生异常综合征与急性髓系白血病患者,参考不同治疗方式分为研究组(40例)与对照组(40例),研究组选用地西他滨联合全程HA方案治疗,对照组选用地西他滨联合半程HA方案治疗;比较两组治疗后血小板、中性粒细胞减少持续时间、缓解率、总反应率及毒副反应发生率。结果:研究组治疗后血小板、中性粒细胞减少持续时间与缓解率、总反应率及毒副反应发生率依次为(10.18±0.98)d、(11.57±1.34)d、70.00%、82.50%、7.50%,对照组治疗后血小板、中性粒细胞减少持续时间与缓解率、总反应率及毒副反应发生率依次为(16.45±1.46)d、(18.03±1.92)d、30.00%、60.00%、25.00%。研究组较对照组治疗后血小板、中性粒细胞减少持续时间更短,缓解率及总反应率更高,毒副反应发生率更低(P<0.05)。结论:地西他滨联合全程HA方案治疗骨髓增生异常综合征和急性髓系白血病的效果优于地西他滨联合半程HA方案,且毒副反应少。     

Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia

Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia.     

Acute myeloid leukemia with translocation (1;21)

Advancement in genetic and molecular biology techniques has greatly helped our understanding of various diseases, especially hematological disorders. We describe a case of primary myelofibrosis (PMF) that transformed into acute myeloid leukemia with a very rare and unusual genetic translocation of (1;21). There are only five reported cases of this translocation in acute myeloid leukemia (AML) or myelodysplastic syndrome but none of them transformed from PMF. This case not only highlights the importance of rare genetic translocations but also provides the natural history of the disease and its poor prognosis. To the best of our knowledge our patient is the first reported case of AML transformed from PMF to have this unique translocation of (1;21).     

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.     

Blood group change in a patient with blastic transformation of a myelodysplastic syndrome

Loss of certain red blood cell antigens has been described in patients with acute myelocytic leukemia (AML). This paper describes the loss of blood group A antigen in a patient with AML. The acute leukemia in this patient was preceded by a myelodysplastic syndrome for several months. At the time of diagnosis the patient's red cells showed the 0 Rh(D)+ phenotype. After induction of complete remission with two courses of Daunorubicin, Cytosin-arabinosid, and Etoposid his blood group reverted to A2. Serological studies including saliva analysis revealed that the original blood group was very likely A.     

Addition of Arsenic Trioxide into Induction Regimens Could Not Accelerate Recovery of Abnormality of Coagulation and Fibrinolysis in Patients with Acute Promyelocytic Leukemia

Aim

All-trans retinoic acid combined to anthracycline-based chemotherapy is the standard regimen of acute promyelocytic leukemia. The advent of arsenic trioxide has contributed to improve the anti-leukemic efficacy in acute promyelocytic leukemia. The objectives of the current study were to evaluate if dual induction by all-trans retinoic acid and arsenic trioxide could accelerate the recovery of abnormality of coagulation and fibrinolysis in patients with acute promyelocytic leukemia.

Methods

Retrospective analysis was performed in 103 newly-diagnosed patients with acute promyelocytic leukemia. Hemostatic variables and the consumption of component blood were comparably analyzed among patients treated by different induction regimen with or without arsenic trioxide.

Results

Compared to patients with other subtypes of de novo acute myeloid leukemia, patients with acute promyelocytic leukemia had lower platelet counts and fibrinogen levels, significantly prolonged prothrombin time and elevated D-dimers (P<0.001). Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification presented lower initial fibrinogen level than that of low-risk group (P<0.05). After induction treatment, abnormal coagulation and fibrinolysis of patients with acute promyelocytic leukemia was significantly improved before day 10. The recovery of abnormal hemostatic variables (platelet, prothrombin time, fibrinogen and D-dimer) was not significantly accelerated after adding arsenic trioxide in induction regimens; and the consumption of transfused component blood (platelet and plasma) did not dramatically change either. Acute promyelocytic leukemia patients with high or intermediate risk prognostic stratification had higher platelet transfusion demands than that of low-risk group (P<0.05).

Conclusions

Unexpectedly, adding arsenic trioxide could not accelerate the recovery of abnormality of coagulation and fibrinolysis in acute promyelocytic leukemia patients who received all-trans retinoic acid combining chemotherapy.     

Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome

Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3), both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.     

Characterization of genetic instability in radiation- and benzene-induced murine acute leukemia.

This study, using the CBA/Ca mouse as a model, compares genetic lesions associated with radiation- and benzene-induced acute leukemias. Specific types of leukemia included in the analyses are radiation-induced acute myeloid leukemia (ML), and benzene-induced lymphoblastic leukemias, lymphomas, or mix-lineage leukemias. These leukemias have histopathological characteristics similar to those seen in human acute leukemias. G-band cytogenetic analysis showed that specific deletions involving regions D-E of one copy of mouse chromosome 2 [del(2)(D-E)] were frequently associated in both radiation- and benzene-induced acute leukemias. In addition, translocations of chr2(D-E) were also observed in some cases. These results suggest an important role of chr2 (D-E) deletions and translocations in the development of radiation- and benzene-induced murine acute leukemias. Fluorescence in situ hybridization with DNA probes specific for 2(D-E), constructed in our laboratory by means of chromosomal microdissection and PCR amplification, also demonstrate 2(D-E) deletions and/or translocations in these leukemic cells. Aneuploidy of chromosomes 3, 15, 16, and Y were also frequently detected in benzene-induced leukemic cells with or without lesions on chr2. These cytogenetic findings support the previous observations that metabolites of benzene lead to spindle-fiber disruption or abnormal cytokinesis in exposed animals. In summary, genetic instabilities observed in leukemic cells isolated from mice that had developed leukemia after exposure to radiation or benzene are syntenic with those frequently detected in patients with myelodysplastic syndrome, acute ML, and acute lymphoblastic leukemia. Thus, the CBA/Ca mouse has several characteristics that make it an excellent model for the study of radiation or benzene leukemogenesis in humans.     

The peculiarities of cytogenetic changes in different types of myelodysplastic syndrome

A cytogenetic study of bone marrow aspirate from 32 patients with different types of myelodysplastic syndrome (MDS) has been carried out. The patients were from eight regions of Ukraine. Chromosome deletions prevailed in the spectrum of karyotype changes. The largest number of chromosome abnormalities was revealed in patients with a refractory anemia with an excess of blasts (66.6% of cases). Chromosomal changes that involved three or more chromosomes occurred among 27% of all karyotype changes examined by us. Transformation of myelodysplastic syndrome to acute myeloid leukemia (AML) was found in 5 patients (45.4% of the cases) among 11 patients with abnormal karyotypes. We propose that cytogenetic confirmation of increased apoptosis in the bone marrow from the myelodysplastic syndrome patients is a phenomenon of chromosome fragmentation. The risk of transformation of myelodysplastic syndrome to acute myeloid leukemia was measured with the use of a new international score system, IPSS.     

Gangliosides of human acute leukemia cells

We characterized the gangliosides from cells of eight patients with different forms of acute leukemia (four lymphoblastic, four nonlymphoblastic) by thin-layer chromatography and high-performance liquid chromatography combined with glycosidase treatment. Our analysis indicated both quantitative and qualitative differences between the gangliosides of acute leukemia and those of normal leukocytes: 1, the absolute amount of ganglioside was decreased in the acute leukemia cells; 2, in general, acute leukemias had a more simplified ganglioside pattern in that they contained a greater proportion of the short-chain ganglioside, II3NeuAc-LacCer (GM#); 3, all of the acute leukemia cells contained reduced quantities of the ganglioside N-acetylneuraminosyl-lactotriaosylceramide, a compound previously found only in normal leukocytes; and 4, a disialylated ganglioside, II3(NeuAc)2-LacCer (GD3), which is not found in normal leukocytes, was isolated from the cells of one patient with acute nonlymphoblastic leukemia. These findings demonstrate important differences between the gangliosides of acute leukemia cells and normal leukocytes.     

ICF syndrome (immunodeficiency,centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome

A further patient with the ICF syndrome (immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9 and 16 and facial anomalies) is described. This case is the second to be reported with consanguinity of the parents. This lends support to the theory of autosomal recessive inheritance. The features of the 15 published cases are reviewed. The clinical and cytogenetic characteristics of the syndrome are discussed, and new evidence provided as to the role of centromeres and centric heterochromatin in the production of chromosome aberrations. Correspondence with other authors has made possible a review of the clinical outcome in this condition.     

bcr rearrangement and C-abl gene expression in Ph1-positive hybrid acute leukemia with simultaneous proliferation of lymphoid and myeloid blasts

bcr gene rearrangement and c-abl gene expression were analyzed in a patient with Philadelphia chromosome (Ph1)-positive hybrid acute leukemia with simultaneous proliferation of lymphoid and myeloid blasts. These data were compared with those from a patient with chronic myelogenous leukemia (CML) in mixed crisis. The leukemic cells of both patients showed immuno-phenotypic profiles such as non-T, non-B common ALL with some MPO-positive leukemic cells and rearranged JH genes. On analysis of molecular events associated with the Ph1 chromosome, the leukemic cells of a patient with CML in mixed crisis showed bcr rearrangement and an 8.5-kb bcr-abl chimeric mRNA, but those of a patient with Ph1-positive hybrid acute leukemia showed no 8.5-kb bcr-abl mRNA, as previously reported in a number of Ph1-positive acute lymphoblastic leukemia (ALL) cases. These results revealed that the molecular event found in Ph1-positive ALL is not only restricted to lymphoid lineage but may play an important role in the proliferation of the myeloid lineage.     

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.     

Intravascular clotting activation and bleeding in patients with hematologic malignancies

The association between thrombosis, bleeding and neoplastic disease is well recognized. There are distinctive features of the thrombotic and bleeding complications associated with specific hematologic malignancies. A number of procoagulants can initiate intravascular clotting including tissue factor, cancer procoagulant and interleukin-1. The hematologic malignancy most often associated with intravascular clotting and bleeding is acute promyelocytic leukemia. The pathogenesis of the life-threatening bleeding disorder associated with this uncommon subtype of acute myeloid leukemia (AML) is complex and involves disseminated intravascular coagulation, fibrinolysis and proteolysis. Both all-trans retinoic acid and arsenic trioxide result in relatively rapid resolution of the coagulopathy. Intravascular clotting may also be induced by hyperleukocytosis in AML and by the hyperviscosity syndrome observed in multiple myeloma and Waldenstr?m's macroglobulinemia. In the setting of hematologic malignancies, when thromboembolic complications occur, the presence of comorbid thrombophilic conditions should be excluded. Abnormal platelet production and function contribute to the development of thrombosis in patients with myeloproliferative disorders. The Budd-Chiari syndrome may be observed in patients with myeloproliferative disorders. A number of medications have thrombogenic potential, including corticosteroids, thalidomide, L-asparaginase, all-trans retinoic acid and arsenic trioxide.     

Results of randomized trials of immunotherapy for acute leukemia

Summary For more than a decade clinical trials have attempted to define the role of immunotherapy in the treatment of patients with acute leukemia. Based on animal studies which indicated that non-specific immune stimulation had an antitumor effect if the tumor burden was small, the use of immunotherapy during remission in patients with acute leukemia seemed appropriate following the initial report of the success of bacillus Calmette-Guerin (BCG) in prolonging remission duration and survival in acute lymphoblastic leukemia. Therefore a series of randomized clinical trials was initiated to confirm these original observations. In four studies comparing BCG inoculations, with or without allogeneic leukemia cells, and chemotherapy or no therapy, no advantage of immunotherapy was noted. Immunotherapy appeared to be equally as good as chemotherapy. A combination of BCG and chemotherapy showed some advantage in one study, but no advantage was noted in two other studies.In acute myeloblastic leukemia several randomized trials suggested that BCG or one of its derivatives when given alone, in combination with allogeneic cells, or with chemotherapy had a marginal effect in prolonging remission duration and survival when compared to chemotherapy or rno therapy.In conclusion, immunotherapy during remission has marginal activity in acute leukemia.     

Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome

ICF (Immunodeficiency, Centromeric instability and Facial anomalies) syndrome is a rare autosomal recessive disease caused by mutations in the DNA methyltransferase gene DNMT3B. To investigate the function of Dnmt3b in mouse development and to create animal models for ICF syndrome, we have generated three mutant alleles of Dnmt3b in mice: one carrying a deletion of the catalytic domain (null allele) and two carrying ICF-like missense mutations in the catalytic domain. The Dnmt3b null allele results in embryonic lethality from E14.5 to E16.5 with multiple tissue defects, including liver hypotrophy, ventricular septal defect and haemorrhage. By contrast, mice homozygous for the ICF mutations develop to term and some survive to adulthood. These mice show phenotypes that are reminiscent of ICF patients, including hypomethylation of repetitive sequences, low body weight, distinct cranial facial anomalies and T cell death by apoptosis. These results indicate that Dnmt3b plays an essential role at different stages of mouse development, and that ICF missense mutations cause partial loss of function. These mutant mice will be useful for further elucidation of the pathogenic and molecular mechanisms underlying ICF syndrome.     

Thrombotic occlusion of the ostial left main coronary artery in a patient with acute coronary syndrome

Ostial left main coronary artery (LMCA) occlusion is rarely seen in patients with acute coronary syndrome. Acute coronary syndrome resulting from an LMCA occlusion is associated with a significant morbidity and mortality rate, if it is managed with fibrinolysis. Electrocardiography can predict LMCA occlusion in patients with acute coronary syndrome. We report a 52-year-old male who presented with acute coronary syndrome and ostial LMCA occlusion. (Neth Heart J 2009;17: 295–6.)     

Myelogenous leukemia and electric blanket use

In a case-control study of adult acute and chronic myelogenous leukemia in Los Angeles County, we tested the hypothesis that excess exposure to electromagnetic fields from electric blankets was associated with risk of leukemia. We did this by studying 116 cases of acute myelogenous leukemia (AML) and 108 cases of chronic myelogenous leukemia (CML) along with matched neighborhood controls. The cases and controls were queried as to electric blanket use and the risks computed. For AML the risk was 0.9 (95% CI 0.5-1.6) and for CML the risk was 0.8 (95% CI 0.4-1.6). Cases did not differ from controls by duration of use, year of first regular use, year since last use, or socioeconomic status. Our best estimates of exposure indicate that electric blanket use increases overall exposure to electric fields by less than 50% and magnetic fields by less than 100%. We conclude that there is no major leukemogenic risk associated with electric blanket use in Los Angeles County.