Home About us Contact
|
Home About us Contact | ||
|
|
||
Lymphoblastic Leukemia (lymphoblastic + leukemia)
Kinds of Lymphoblastic Leukemia Selected AbstractsHematological malignancies in the island of Sardinia, 1974,1993: age and sex distributions and temporal changes in incidenceHEMATOLOGICAL ONCOLOGY, Issue 3 2004G. Broccia Abstract We have collected, by an active retrospective survey, all the cases of hematologic malignancies (HM) newly diagnosed during the time period 1974,1993 in the resident population of Sardinia. Diagnosis was deemed valid, after consultation of clinical records, in more than 90% of the 7264 collected cases. The number of newly diagnosed cases by year more than doubled during the 20-year period investigated. This striking increase can be only partially accounted for by ageing of population. Indeed, age-specific and age-adjusted rates of most of HM increased during this period, although Hodgkin Disease (HD), Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL) were notable exceptions. The observed increase in rates is likely, in a large part, to be fictitious, due to easier access to a health care system, which in the meantime, improved its diagnostic efficiency. This was particularly evident for Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM) and some others myelo- and lympho-proliferative disorders, but its relevance declined after 1984,1989. A likely true increase in occurrence was evidenced for Non-Hodgkin Lymphomas (NHL) and similarly, although to a lesser extent and more doubtful, for Myelodysplasias (MDS) and Acute Myeloid Leukemia (AML). At the end of the studied period each type of HM presented age and sex distributions and age-adjusted rates that show only minor differences from those reported for other western countries. No argument emerged to suggest that any genetic peculiarities of the Sardinian population might have affected the occurrence of HM. The confounding effects of improved diagnostic efficiency have prevented a reliable assessment of influence on incidences of environmental and socio-economic changes that, in relatively recent times, have occurred in Sardinia. Copyright © 2005 John Wiley & Sons, Ltd. [source] Successful Application of OPLS-DA for the Discrimination of Wild-Type and Mutated Cells in Acute Lymphoblastic LeukemiaMOLECULAR INFORMATICS, Issue 8 2009Claudio, Giuseppe Molteni Abstract OPLS-DA was successfully applied to select of a limited number of gene transcripts necessary to discriminate wild type and mutated cells in ALL patients. In the above list it was possible to identify candidate genes that could be involved in the molecular mechanisms linking PTPN11 and RAS mutations to B-ALL genesis. OPLS-DA and SIMCA classification provide a set of 50 and 77 variables respectively suitable to discriminate wild type from mutated cells in ALL patients. [source] Successful Treatment of Severe Iatrogenic Calcinosis Cutis with Intravenous Sodium Thiosulfate in a Child Affected by T-Acute Lymphoblastic LeukemiaPEDIATRIC DERMATOLOGY, Issue 3 2009Colombatti Raffaella M.D., Ph.D. We describe a 5-year-old boy with acute lymphoblastic leukemia who developed severe calcinosis cutis in the right forearm and hand, and in the left leg and foot after extravasation of calcium gluconate during treatment for tumor-lysis-syndrome-related hypocalcaemia. Surgical debridement, local wound care, hyperbaric oxygen therapy, and sodium thiosulfate infusion achieved a complete healing of all lesions in an eight-month period with a short discontinuation of chemotherapy. No functional or sensitive impairment remained. [source] Modulation of antigen expression in B-cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug-induced regulatory phenomenon.CYTOMETRY, Issue 3 2010Results of the AIEOP-BFM-ALL-FLOW-MRD-Study Group Abstract Background: Changes of antigen expression on residual blast cells of acute lymphoblastic leukemia (ALL) occur during induction treatment. Many markers used for phenotyping and minimal residual disease (MRD) monitoring are affected. Glucocorticoid (GC)-induced expression modulation has been causally suspected, however, subclone selection may also cause the phenomenon. Methods: We investigated this by following the phenotypic evolution of leukemic cells with flow cytometry from diagnosis to four time points during and after GC containing chemotherapy in the 20 (of 360 consecutive) B-cell precursor patients with ALL who had persistent MRD throughout. Results: The early expression changes of CD10 and CD34 were reversible after stop of GC containing chemotherapy. Modulation of CD20 and CD45 occurred mostly during the GC phase, whereas CD11a also changed later on. Blast cells at diagnosis falling into gates designed according to "shifted" phenotypes from follow-up did not form clusters and were frequently less numerous than later on. Conclusions: Our data support the idea that drug-induced modulation rather than selection causes the phenomenon. The good message for MRD assessment is that modulation is transient in at least two (CD10 and CD34) of the five prominent antigens investigated and reverts to initial aberrant patterns after stop of GC therapy, whereas CD20 expression gains new aberrations exploitable for MRD detection. © 2010 Clinical Cytometry Society [source] Overexpression of CD49f in precursor B-cell acute lymphoblastic leukemia: Potential usefulness in minimal residual disease detectionCYTOMETRY, Issue 2 2009Joseph A. DiGiuseppe Abstract Background: The persistence of minimal residual disease (MRD) following therapy is an established prognostic factor in precursor B-cell acute lymphoblastic leukemia (pB-ALL). Detection of MRD in pB-ALL by flow cytometric immunophenotyping requires demonstration of abnormal antigen expression in leukemic B-cell precursors relative to that of normal B-cell precursors. The gene encoding CD49f (integrin ,-6) is one of several whose overexpression in pB-ALL at diagnosis has been associated with the subsequent detection of MRD. However, whether CD49f might be a useful reagent in the immunophenotypic detection of MRD in pB-ALL has not been evaluated. Methods: We evaluated CD49f expression by 4-color flow cytometry in normal B-cell precursors, and in a series of cases of pB-ALL, both at diagnosis and at intervals following the initiation of therapy. Results: In 10 control marrow samples, CD49f was undetectable or extremely dim in all but a minor subset of normal CD19+ B-lineage cells, whereas in 11 of 15 cases (73%) of pB-ALL, CD49f was moderate or bright at diagnosis, and persisted or became brighter after initiation of therapy. MRD detected using CD49f corresponded precisely with that obtained using a standard panel of antibodies, and permitted the detection of leukemic populations comprising as little as 0.02% of cells. Of the four pB-ALL cases in which CD49f was undetectable or dim at diagnosis, MRD was detected in two; in one of these, CD49f expression was substantially increased in the leukemic cells that persisted following initiation of therapy. Conclusions: CD49f is commonly overexpressed in p-B-ALL, and represents a potentially useful marker for the immunophenotypic detection of MRD. © 2008 Clinical Cytometry Society How to cite this article: DiGiuseppe JA, Fuller SG, Borowitz MJ. Overexpression of CD49f in precursor B-cell acute lymphoblastic leukemia: potential usefulness in minimal residual disease detection. Cytometry Part B 2008. [source] Prednisone induces immunophenotypic modulation of CD10 and CD34 in nonapoptotic B-cell precursor acute lymphoblastic leukemia cells,CYTOMETRY, Issue 3 2008Giuseppe Gaipa Abstract Background: Immunophenotypic modulation is induced by steroids in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients during remission induction therapy. Methods: We cultured BCP-ALL blasts from diagnostic bone marrow (BM) samples (n = 20) in the presence of prednisone on stroma layer obtained from BM-derived mesenchymal cells to maintain viability. Antigen expression was assessed by multiparametric flow cytometry. Results: Leukemia samples that sustained the treatment in vitro with prednisone, showed significative reduction of CD10 and CD34 expression compared with control, and it was comparable with that observed in residual leukemic cells of the same patients in BM at day 15 of treatment. Modulated cells were viable as determined by Annexin V staining and preserved light scattering properties. Of note, the extent of antigen modulation in vitro correlated with response to prednisone in vivo. Conclusions: The prednisone-induced immunophenotypic modulation can be reproduced in vitro and this phenomenon may reflect sensitivity to chemotherapy. © 2008 Clinical Cytometry Society [source] Multiparametric analysis of normal and postchemotherapy bone marrow: Implication for the detection of leukemia-associated immunophenotypes,CYTOMETRY, Issue 1 2008D. Olaru Abstract Background: The knowledge of normal marrow is mandatory to assess the malignant counterpart of normal cells and define leukemia-associated immunophenotypes (LAIPs). In this study, the expression of a variety of antigens expressed in normal and postchemotherapy bone marrow (BM) was analyzed to provide a frame of reference for the identification of myeloid LAIPs. Methods: Multiparameter four- and six-color flow cytometry was used to define antigen combinations totally absent or present at very minimal levels in marrow cells of normal individuals (n = 20) and patients receiving chemotherapy for acute lymphoblastic leukemia (n = 20). Immature (blast) cells were gated according to CD45/SSC properties. Fifty-three acute myeloid leukemia (AML) samples were studied in six-color combinations. Results: In six-color flow cytometry, 47 phenotypes were totally absent from blast gate in all normal samples. Forty-one other phenotypes were identified in less than 0.05% of blast cells. There was no difference between normal and postchemotherapy BMs. The four-color panel allowed to identify only 30 phenotypes present at a frequency <0.05%. Using the six-color panel, 58% of the absent or infrequent phenotypes in normal BM were found in at least one of 53 AML samples. All AML cases exhibited at least one LAIP. Conclusion: Our results show that the ability to distinguish leukemic from healthy cells is considerably increased by a six-color approach. Furthermore, these absent or infrequent phenotypes in normal BM are identified in AML and can be utilized for minimal residual disease study. © 2007 Clinical Cytometry Society [source] Increased immature hematopoietic progenitor cells CD34+/CD38dim in myelodysplasiaCYTOMETRY, Issue 2 2006Mariela B. Monreal Abstract Background Myelodysplastic syndromes (MDS) are clonal disorders affecting hematopoietic progenitor cells (HPC). Despite the relevance of clonal CD34+ cells in developing MDS, only few studies analyze the phenotype of this cell population. The aim of this study was to evaluate phenotypic changes on HPC in MDS that could reflect abnormalities in the differentiation process of stem cells. Methods We analyzed the expression of CD38 and HLA-DR on CD34+ cells by flow cytometry in 36 patients with MDS, as well as in healthy donors (n = 12) and patients with other hematological disorders: non-Hodgkin lymphomas and multiple myeloma, both in complete remission (CR) (n = 32); acute lymphoblastic leukemia in CR (n = 17); de novo acute myeloblastic leukemia (AML) at diagnosis (n = 22) and in CR (n = 37); and AML secondary to MDS at diagnosis (n = 19). Cases with available karyotype were grouped according to the International Prognostic Scoring System (IPSS). Results Compared to normal BM, the fraction of immature HPC, characterized as CD34+bright, intermediate FSC/SSC, and CD38dim, was significantly increased in high risk MDS and secondary AML, but not in low risk MDS, (P , 0.001, P = 0.03, and P = 0.7). De novo AML showed decreased immature HPC. High numbers of immature HPC correlated with higher IPSS risk groups (P = 0.05) and showed significant impact on disease progression (P = 0.03). Conclusion Our study confirms that evaluation of CD38 expression pattern on HPC is an easy and reproducible test that allows evaluating the immature subset of progenitor cells. Increased immature HPC in high risk MDS and secondary AML may reflect blocked differentiation of CD34+ cells in these diseases. © 2006 International Society for Analytical Cytology [source] Delayed neurotoxicity associated with therapy for children with acute lymphoblastic leukemiaDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 3 2006Peter D. Cole Abstract Most children diagnosed today with acute lymphoblastic leukemia (ALL) will be cured. However, treatment entails risk of neurotoxicity, causing deficits in neurocognitive function that can persist in the years after treatment is completed. Many of the components of leukemia therapy can contribute to adverse neurologic sequelae, including craniospinal irradiation, nucleoside analogs, corticosteroids, and antifolates. In this review, we describe the characteristic radiographic findings and neurocognitivie deficits seen among survivors of childhood ALL. We summarize what is known about the pathophysiology of delayed treatment-related neurotoxicity, with a focus on the toxicity resulting from pharmacologic disruption of folate physiology within the central nervous system. Finally, we suggest testable strategies to ameliorate the symptoms of treatment-related neurotoxicity or decrease its incidence. MRDD Research Reviews 2006;12:174,183. © 2006 Wiley-Liss, Inc. [source] Primary relapse of acute lymphoblastic leukemia in a cervical smear: A case reportDIAGNOSTIC CYTOPATHOLOGY, Issue 7 2006Akiko Ikuta M.D. Abstract Uterine cervix and corpus are rarely the initial site of relapse in leukemia or lymphoma. We report herein a case of uterine cervical relapse with B-cell acute lymphoblastic leukemia (ALL). The patient, a 60-yr-old woman, had a history of ALL that had been in remission for 2 yr after chemotherapy. She presented with a chief complaint of genital bleeding. In a routine cervico-vaginal Papanicolau smear, abundant atypical lymphoid cells with round-to-oval nuclei, scant cytoplasm, and high nuclear to cytoplasmic ratios was observed. The nuclei of these cells had fine and dark chromatin and thickened nuclear membranes, with one or several nucleoli being visible. Biopsy under colposcope was performed, and a diagnosis of relapse of ALL was confirmed. The ongoing genital bleeding presented a problem with clinical management of the patient. It was decided to proceed with hysterectomy to end that problem and thereafter proceed with therapy directed against the leukemia. Our results suggest that in patients with known extrauterine cancer, the presence of malignancy in uterine cellular samples provides information regarding the extent of the neoplasm. Diagn. Cytopathol. 2006;34:499,502. © 2006 Wiley-Liss, Inc. [source] Novel agents to override imatinib resistance mechanismsDRUG DEVELOPMENT RESEARCH, Issue 7 2008Asumi Yokota Abstract Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results from the Philadelphia chromosome (Ph) created through translocation of human chromosomes 9 and 22. The resulting Bcr-Abl fusion protein has constitutively high tyrosine kinase activity that causes transformation of hematopoietic stem cells. Imatinib mesylate (IM) was developed as a specific Bcr-Abl kinase inhibitor and is efficacious in treating Ph-chromosome-positive (Ph+) leukemias such as CML and Ph+ acute lymphoblastic leukemia (ALL). Within a few years of its introduction to the clinic, IM has dramatically altered the first-line therapy for CML. Although most newly diagnosed CML patients in the chronic phase (CP) achieved durable responses when treated with IM, resistance to IM has become a major problem in patients with advanced-stage disease. The most important mechanism of IM resistance are point mutations within the Abl kinase domain; therefore, there is an urgent need for novel agents that can inhibit mutated Bcr-Abl. In this review, we describe novel Bcr-Abl tyrosine kinase inhibitors, the so-called "Super Gleevec" inhibitors. Drug Dev Res 69:398,406, 2008. © 2008 Wiley-Liss, Inc. [source] FLT3 Antibody-based therapy for leukemiaDRUG DEVELOPMENT RESEARCH, Issue 6 2006Yiwen Li Abstract Technological advances in antibody generation and production have facilitated recent clinical and commercial success with antibody-based cancer therapeutics. The class III receptor tyrosine kinase FLT3 is highly expressed on the blast cells in most cases of acute myelogenous leukemia (AML) and B-cell acute lymphoblastic leukemia (ALL). Activating mutations of FLT3 are detected in approximately 37% AML patients. FLT3 expression in normal tissue is limited to myeloid and B-cell precursor cells. Therefore, over-expressed or mutated FLT3 is an attractive target for therapeutic intervention using monoclonal antibodies. This review will discuss recent progress in the development of anti-FLT3 antibodies as well as their therapeutic potentials in the treatment of AML and other hematological malignancies. Drug Dev. Res. 67:495,500, 2006. © 2006 Wiley-Liss, Inc. [source] Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemiaENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2004Renata Canalle Abstract Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Although exposure to environmental agents appears to predispose individuals to this disease, little attention has been paid to the role of genetic susceptibility to environmental exposures in the etiology of childhood ALL. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1, and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, alcoholic drinks, pesticides, and environmental pollutants. Polymorphisms in the genes coding for these enzymes have been associated with increased susceptibility to different cancers, including hematologic malignancies. To investigate whether these polymorphisms represent risk-modifying factors for childhood ALL, a study was conducted involving 113 Brazilian patients of childhood ALL and 221 controls with similar ethnic backgrounds. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of ALL (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.1,6.8; P = 0.04). No difference was found in the prevalence of the GSTM1 and GSTT1 null genotypes between ALL patients and the controls, and no association was found between CYP1A1*2 and CYP2E1*3 variants and ALL. However, when the mutant CYP1A1 and CYP2E1 alleles were considered together with the GSTM1 and GSTP1 risk-elevating genotypes, the risk of ALL was increased further (OR = 10.3; 95% CI = 1.0,111.8; P = 0.05), suggesting a combined effect. These results imply that genetic variants of xenobiotic metabolizing genes influence the risk of developing childhood ALL. Environ. Mol. Mutagen. 43:100,109, 2004. © 2004 Wiley-Liss, Inc. [source] DV-ICE, intensive induction and early transplantation for adult patients with acute lymphoblastic leukemia: a phase II studyEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2009Christine Dudler Abstract Objectives:, Eighty percent of adult patients with acute lymphoblastic leukemia (ALL) achieve a complete remission (CR) but only 30,40% are long term survivors. Best treatment strategies remain to be defined. The role of induction intensity, first remission hematopoietic stem cell transplantation (HSCT) and maintenance chemotherapy continues to be discussed. We tested a strategy of high intensity treatment of short duration followed by HSCT. Patients and methods:, This prospective phase II study used induction with DV-ICE followed by immediate allogeneic or autologous HSCT (depending on donor availability) without additional consolidation or maintenance treatment. DV-ICE consisted of dexamethasone, vincristine, idarubicin, etoposide, and conventional dose cytosine arabinoside; HSCT was planned immediately if CR was achieved or after an additional course of intermediate high dose cytosine arabinoside and etoposide for patients with induction failure. A total of 42 consecutive patients between 17 and 67 yr of age (median 43 yr) were enrolled. Of the 42 patients, 57% were male, 76% had B-lineage ALL, 19% T-lineage ALL and two patients biphenotypic ALL. 29% were Ph+; 7% had 11q23 and 45% had a normal karyotype. CNS involvement was found in three patients. Results:, Thirty-three patients (79%) achieved a CR, 24 patients after induction I or II and nine patients after rescue HSCT. 31 patients received a HSCT (seven autologous and 24 allogeneic). 11 patients did not receive a HSCT because of early death in nine (treatment toxicity in five, refractory disease in four), one patient refused transplantation, one patient was not suitable. Disease-free survival (DFS) of the entire cohort was 46% (95% CI ±16%) at 1 yr and 16% (±13%) at 5 yr. Overall survival (OS) was 63% (±15%) at 1 yr and 23% (±15%) at 5 yr, with a median follow-up of surviving patients of 55 (4,136) months. Neither disease subtype, cytogenetic abnormalities nor patient age or gender was significantly associated with survival. Conclusions:, Intensive induction using DV-ICE followed by early transplantation without treatment beyond 4 months failed to improve outcome compared with standard treatment. [source] Results of the PETHEMA ALL-96 trial in elderly patients with Philadelphia chromosome-negative acute lymphoblastic leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2007Juan-Manuel Sancho Abstract Background and aim:,Only 20,30% of elderly patients with acute lymphoblastic leukemia (ALL) are enrolled in clinical trials because of co-morbid disorders or poor performance status. We present the results of treatment of Philadelphia chromosome-negative (Ph,) ALL patients over 55 yr treated in the PETHEMA ALL-96 trial. Patients and methods:,From 1996 to 2006, 33 patients 55 yr with Ph, ALL were included. Induction therapy was vincristine, daunorubicin, prednisone, asparaginase, and cyclophosphamide over 5 weeks. Central nervous system (CNS) prophylaxis involved triple intrathecal (IT) therapy, 14 doses over the first year. Consolidation-1 included mercaptopurine, methotrexate, teniposide and cytarabine, followed by one consolidation-2 cycle similar to the induction cycle. Maintenance consisted of mercaptopurine and methotrexate up to 2 yr in complete remission (CR) with monthly reinduction cycles (vincristine, prednisone and asparaginase) during the first year. Results:,Median (range) age was 65 yr (56,77). Phenotype (30 patients): early-pre-B 7, common/pre-B 18, T 5. Cytogenetics (28 patients): normal 12, complex 10, t(4;11) 2 and other 4. CR was achieved in 19/33 (57.6%) patients, early death occurred in 12 (36.4%) and 2 (6%) were resistant. Overall survival and disease-free survival probabilities (2 yr, 95% CI) were 39% (21%,57%) and 46% (22%,70%), respectively (median follow up of 24 months). Removal of asparaginase and cyclophosphamide from the induction decreased induction death (OR 0.119, CI 95% 0.022,0.637, P = 0.013) and increased survival (20% vs. 52%, P = 0.05). Conclusions:,The prognosis of elderly Ph, ALL patients is poor. In this study, less intensive induction decreased toxic death, allowing delivery of planned consolidation therapy and increased survival probability. [source] Placenta growth factor stimulates the growth of Philadelphia chromosome positive acute lymphoblastic leukemia cells by both autocrine and paracrine pathwaysEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2005Toshiko Ikai Abstract:, Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph+) ALL than in Ph, ALL cases. On the other hand, expression level of VEGF was not different between Ph+ and Ph, cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph+), and Nalm6 (Ph,). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph+ ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph+ ALL. [source] Expression of DNA repair gene Ku80 in lymphoid neoplasmEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2005Tsai-Yun Chen Abstract:,Objectives:,Ku, a heterodimer of KU70 and Ku80 that binds to double-strand DNA breaks (DSBs) and activates the catalytic subunit (DNA-PKcs) when DNA is bound, is essential in DSB repair and V(D)J recombination. Ku80 is a putative tumor suppressor gene that might play an important role in drug resistance. Our aim was to determine the role of Ku80 in lymphoid malignancy. Patients and methods:,Competitive reverse transcription-polymerase chain reaction assays were performed and the expression levels of Ku80 were measured in normal peripheral blood mononuclear cells (n = 9) and malignant cells from 25 patients with acute lymphoblastic leukemia (ALL) (14 children, 11 adults), and chronic lymphoproliferative disorders (n = 6). The Ku80 transcripts were sequencing for the possibility of mutation. Results:,No mutation or Ku80 variant at the RNA level was seen in any patient samples or in the Raji or CCRF-CEM cell lines. In Ku80 expression, 8.8-, 1.9-, and 6.2-fold mean increases were seen in adult, pediatric ALL, and chronic lymphoid malignancies compared with the control. The Ku80 was significantly higher in adult than in pediatric ALL (P = 0.02). The amount of Ku80 expression in ALL was moderately correlated with peripheral white blood cell counts, but not with Ki67 labeling index. High Ku80 expressers (higher than the mean of all patients with ALL) tended to respond poorly to therapy: Only 22% of high Ku80 expressers achieved durable complete remission compared to 62% of low expressers. Conclusions:,Our study suggests that Ku80 might contribute to generally poor prognoses in adult ALL. [source] Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2004Krzysztof Jamroziak Abstract: The significance of genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Polymorphisms of genes encoding for xenobiotics and drug transporters are potential factors, which can influence the risk of developing ALL and its clinical outcome. P-glycoprotein (P-gp) is an adenosine triphosphate-binding cassette (ABC)-family transporter involved in protection against xenobiotics and multi-drug resistance. Recently, the single-nucleotide polymorphism C3435T of MDR1 gene has been found to be associated with altered tissue expression and function of P-gp. To evaluate whether C3435T MDR1 polymorphism is associated with the occurrence and outcome of ALL, 113 children with ALL (median age 5.1 yr) and 175 healthy individuals of Polish Caucasian origin were studied by polymerase chain reaction-restriction fragment-length polymorhism (PCR-RFLP) assay. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (OR, 95% CI; 1.8, 1.1,3.1; P = 0.037). Besides, the analysis of factors influencing clinical outcome of our ALL patient cohort showed that CC genotype carriers had significantly lower event-free survival probability (pEFS) (0.62 vs. 0.87; P = 0.007) and overall survival probability (pOS) (0.72 vs. 0.91; P = 0.006). The Cox proportional hazards model-based analysis revealed that the hazard ratios for lower pEFS and lower pOS among CC homozygous subjects were 3.9 (P = 0.008) and 3.3 (P = 0.02), respectively. In conclusion, the results of the present study provide evidence that C3435T MDR1 polymorphism may involve both the susceptibility to and the clinical outcome of childhood ALL. Carriers of the TT genotype are more at risk of developing ALL than other individuals, whereas CC genotype carriers are supposed to have worse prognosis. [source] Recurrent palmar,plantar erythrodysaesthesia following high-dose cytarabine treatment for acute lymphoblastic leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5-6 2002Julie H. Crawford Abstract: Palmar,plantar erythrodysaesthesia (PPE) is an uncommon cutaneous complication of cytotoxic chemotherapy which generally presents as a painful erythema involving the palms and soles. It has been suggested that PPE caused by cytarabine does not recur with subsequent cytarabine re-challenge. We report a patient with recurrent, increasingly severe episodes of PPE, ultimately complicated by a severe bullous eruption, following successive cycles of high-dose cytarabine for the treatment of acute lymphoblastic leukaemia. Contrary to previous recommendations, our experience cautions against the further use of high-dose cytarabine in patients who develop PPE, and is a timely reminder of the potential toxicity of this agent, which is now increasingly being used as first-line treatment in the management of haematologic malignancies. [source] Structural and functional insights into Erwinia carotovora l -asparaginaseFEBS JOURNAL, Issue 17 2008Anastassios C. Papageorgiou Bacterial l -asparaginases are enzymes that catalyze the hydrolysis of l -asparagine to aspartic acid. For the past 30 years, these enzymes have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia. Their intrinsic low-rate glutaminase activity, however, causes serious side-effects, including neurotoxicity, hepatitis, coagulopathy, and other dysfunctions. Erwinia carotovora asparaginase shows decreased glutaminase activity, so it is believed to have fewer side-effects in leukemia therapy. To gain detailed insights into the properties of E. carotovora asparaginase, combined crystallographic, thermal stability and cytotoxic experiments were performed. The crystal structure of E. carotovoral -asparaginase in the presence of l -Asp was determined at 2.5 Å resolution and refined to an Rcryst of 19.2 (Rfree = 26.6%) with good stereochemistry. Cytotoxicity measurements revealed that E. carotovora asparaginase is 30 times less toxic than the Escherichia coli enzyme against human leukemia cell lines. Moreover, denaturing experiments showed that E. carotovora asparaginase has decreased thermodynamic stability as compared to the E. coli enzyme and is rapidly inactivated in the presence of urea. On the basis of these results, we propose that E. carotovora asparaginase has limited potential as an antileukemic drug, despite its promising low glutaminase activity. Our analysis may be applicable to the therapeutic evaluation of other asparaginases as well. [source] Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: Poor prognosis and prenatal originGENES, CHROMOSOMES AND CANCER, Issue 10 2010Jan Zuna The ETV6/ABL1 (TEL/ABL) fusion gene is a rare aberration in malignant disorders. Only 19 cases of ETV6/ABL1 -positive hematological malignancy have been published, diagnosed with chronic myeloid leukemia, other types of chronic myeloproliferative neoplasm, acute myeloid leukemia or acute lymphoblastic leukemia (ALL). This study reports three new cases (aged 8 months, 5 years, and 33 years) of ALL with the ETV6/ABL1 fusion found by screening 392 newly diagnosed ALL patients (335 children and 57 adults). A thorough review of the literature and an analysis of all published data, including the three new cases, suggest poor prognosis of ETV6/ABL1 -positive acute leukemias. The course of the disease in the two pediatric patients is characterized by minimal residual disease monitoring, using quantification of both the ETV6/ABL1 transcript and immunoreceptor gene rearrangements. Eosinophilia could not be confirmed as a hallmark of the ETV6/ABL1 -positive disease. Studies of neonatal blood spots demonstrated that, in the child diagnosed at five years, the ETV6/ABL1 fusion initiating the ALL originated prenatally. © 2010 Wiley-Liss, Inc. [source] Focal 9p instability in hematologic neoplasias revealed by comparative genomic hybridization and single-nucleotide polymorphism microarray analysesGENES, CHROMOSOMES AND CANCER, Issue 4 2010Anu Usvasalo Copy number losses in chromosome arm 9p are well-known aberrations in malignancies, including leukemias. The CDKN2A gene is suggested to play a key role in these aberrations. In this study overviewing 9p losses in hematologic neoplasias, we introduce the term focal 9p instability to indicate multiple areas of copy number loss or homozygous loss within a larger heterozygous one in 9p. We have used microarray comparative genomic hybridization to study patients with acute lymphoblastic leukemia (ALL, n = 140), acute myeloid leukemia (n = 50), chronic lymphocytic leukemia (n = 20), and myelodysplastic syndromes (n = 37). Our results show that 9p instability is restricted to ALL. In total, 58/140 (41%) patients with ALL had a loss in 9p. The 9p instability was detected in 19% of the patients with ALL and always included homozygous loss of CDKN2A along with loss of CDKN2B. Other possibly important genes included MTAP, IFN, MLLT3, JAK2, PTPLAD2, and PAX5. 13/27 (48%) patients with the instability had the BCR/ABL1 fusion gene or other oncogene-activating translocation or structural aberrations. Two patients had homozygous loss of hsa-mir ,31, a microRNA known to regulate IKZF1. IKZF1 deletion at 7p12.1 was seen in 10 (37%) patients with the 9p instability. These findings suggest that, in ALL leukemogenesis, loss of CDKN2A and other target genes in the instability region is frequently associated with BCR/ABL1 and IKZF1 dysfunction. The multiple mechanisms leading to 9p instability including physical or epigenetic loss of the target genes, loss of the microRNA cluster, and the role of FRA9G fragile site are discussed. © 2009 Wiley-Liss, Inc. [source] Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepitheliomaGENES, CHROMOSOMES AND CANCER, Issue 7 2008Petter Brandal Chromosome banding as well as molecular cytogenetic methods are of great help in the diagnosis of mesenchymal tumors. Myoepithelial neoplasms of soft tissue including myoepitheliomas, mixed tumors, and parachordomas are diagnoses that have been increasingly recognized the last few years. It is still debated which neoplasms should be included in these morphologically heterogeneous entities, and the boundaries between them are not clear-cut. The pathogenetic mechanisms behind myoepithelial tumors are unknown. Only five parachordomas and one mixed tumor have previously been karyotyped, and nothing is known about their molecular genetic characteristics. We present a mesenchymal tumor classified as a myoepithelioma that had a balanced translocation t(1;22)(q23;q12) as the sole karyotypic change. A novel EWSR1-PBX1 fusion gene consisting of exons 1,8 of the 5,-end of EWSR1 and exons 5,9 of the 3,-end of PBX1 was shown to result from the translocation. Both genes are known to be targeted also by other neoplasia-specific translocations, PBX1 in acute lymphoblastic leukemia and EWSR1 in several solid tumors, most of which are malignant. Based on the structure of the novel fusion gene detected, its transforming mechanism is thought to be the same as for other fusion genes involving EWSR1 or PBX1. © 2008 Wiley-Liss, Inc. [source] Intrachromosomal amplification of chromosome 21 (iAMP21) may arise from a breakage,fusion,bridge cycleGENES, CHROMOSOMES AND CANCER, Issue 4 2007Hazel M. Robinson Intrachromosomal amplification of chromosome 21 (iAMP21), involving amplification of the RUNX1 gene and duplication of chromosome 21, dup(21q), defines a new cytogenetic subgroup in B-lineage acute lymphoblastic leukemia (ALL) with a poor prognosis. Characterization of this abnormality has become vital to ensure that the most accurate detection method is used. We have previously defined common regions of amplification and deletion of chromosome 21 in these patients, although the level and extent of amplification within the amplicon was highly variable. This study, using interphase fluorescence in situ hybridization (FISH) with chromosome 21 locus specific probes, substantiated these findings in a large series of patients and confirmed that the amplicon always included RUNX1. Thus, FISH with probes directed to the RUNX1 gene remains the most reliable detection method. Metaphase FISH, supported by G- and multiple color chromosomal banding (mBAND) revealed the patient specific morphology and genetic profile of the dup(21q) chromosomes, as well as the complexity of the intrachromosomal changes giving rise to them. These findings suggested that iAMP21 had arisen from a breakage,fusion,bridge cycle: a mechanism previously described in tumors, which we report for the first time in ALL. © 2007 Wiley-Liss, Inc. [source] Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner geneGENES, CHROMOSOMES AND CANCER, Issue 5 2006Laura J. C. M. van Zutven Chromosome rearrangements are found in many acute leukemias. As a result, genes at the breakpoints can be disrupted, forming fusion genes. One of the genes involved in several chromosome aberrations in hematological malignancies is NUP98 (11p15). As NUP98 is close to the 11p telomere, small translocations might easily be missed. Using a NUP98 -specific split-signal fluorescence in situ hybridization (FISH) probe combination, we analyzed 84 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome with either normal karyotypes or 11p abnormalities to investigate whether there are unidentified 11p15 rearrangements. Neither NUP98 translocations nor deletions were identified in cases with normal karyotypes, indicating these aberrations may be very rare in this group. However, NUP98 deletions were observed in four cases with unbalanced 11p aberrations, indicating that the breakpoint is centromeric of NUP98. Rearrangements of NUP98 were identified in two patients, both showing 11p abnormalities in the diagnostic karyotype: a t(4;11)(q1?3;p15) with expression of the NUP98,RAP1GDS1 fusion product detected in a 60-year-old woman with AML-M0, and an add(11)(p15) with a der(21)t(11;21)(p15;p13) observed cytogenetically in a 1-year-old boy with AML-M7. JARID1A was identified as the fusion partner of NUP98 using 3, RACE, RT-PCR, and FISH. JARID1A, at 12p13, codes for retinoblastoma binding protein 2, a protein implicated in transcriptional regulation. This is the first report of JARID1A as a partner gene in leukemia. © 2006 Wiley-Liss, Inc. [source] Evidence for a single-step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemiaGENES, CHROMOSOMES AND CANCER, Issue 2 2005Kajsa Paulsson High hyperdiploidy (>50 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is characterized by nonrandom multiple trisomies and tetrasomies involving in particular chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21. This characteristic karyotypic pattern, the most common in pediatric ALL, may arise via a tetraploid state with subsequent loss of chromosomes, by sequential gains of chromosomes in consecutive cell divisions, or by simultaneous gain of chromosomes in a single mitosis. These alternatives may be distinguished by investigation of the allelic ratios of loci on the tetrasomic and disomic chromosomes. Previous studies of tetrasomy 21 and of the occurrence of uniparental disomies (UPDs) have suggested that the most likely mechanism is simultaneous gain. However, the other pathways have not been definitely excluded because complete analyses of all disomies and tetrasomies have never been performed. In the present study, we investigated 27 hyperdiploid ALLs by using 58 polymorphic microsatellite markers mapped to 23 of the 24 human chromosomes. Twenty-six tetrasomies were analyzed (involving chromosomes X, 8, 10, 14, 18, and 21), and the frequency of UPDs was determined in 10 cases. In total, 200 chromosomes were studied. Equal allele dosage was observed in 24 of 26 tetrasomies, and only 7 UPDs were found. These data strongly suggest that hyperdiploidy in childhood ALL generally arises by a simultaneous gain of all additional chromosomes in a single abnormal mitosis. © 2005 Wiley-Liss, Inc. [source] A microarray model system identifies potential new target genes of the proto-oncogene HOX11GENES, CHROMOSOMES AND CANCER, Issue 4 2004Katrin Hoffmann HOX11 is a homeobox gene originally identified at a chromosomal breakpoint in T-cell acute lymphoblastic leukemia (T-ALL). It is one of the most frequently deregulated genes in T-ALL, although the precise role of HOX11 in leukemogenesis as well as in normal development remains obscure. To gain more insight into the functional role of HOX11, we utilized a microarray model system to characterize the gene expression network that it directs. Using one of our T-ALL cell lines that had been stably transfected to express HOX11 and high-density oligonucleotide HG-U95A arrays, we identified a large number of differentially expressed genes in response to the enforced expression of HOX11. We focused on examining genes found to be up-regulated according to the microarray analysis and selected three putative target genes, NFKB2, SMARCD3, and NR4A3, for further investigation. We could not only confirm the up-regulation of NR4A3 by an independent method in all clones expressing HOX11, but luciferase reporter assays demonstrated that the effect that HOX11 exerted on the proximal promoter of NR4A3 was dependent on the presence of an intact homeodomain, providing support for the idea that HOX11 manifests its regulatory function via its action as a transcription factor. © 2004 Wiley-Liss, Inc. [source] Comparative expressed sequence hybridization studies of high-hyperdiploid childhood acute lymphoblastic leukemiaGENES, CHROMOSOMES AND CANCER, Issue 3 2004Alicja M. Gruszka-Westwood The functional consequences of a high-hyperdiploid karyotype, found in up to one-third of cases of acute lymphoblastic leukemia (ALL), are unknown. Using the technique of comparative expressed sequence hybridization (CESH), we sought to address the question of whether increased chromosome copies in hyperdiploid ALL lead to increased gene expression. Relative expression of hyperdiploid ALL blasts versus peripheral blood mononuclear cells was analyzed in 18 patients. Common regions of overexpression corresponding to the presence of tri-/tetrasomies included: Xp22.1,22.2, 4q28, 6q14,15, 6q24, 10p13, 14q23,24, 17q21, 18q12, and 21q21, identified in 28,89% of cases. However, increased expression without underlying trisomy occurred at 3p21.3, 7q11.2, 8p21, and 8q24.1 in 39,90% of cases. High expression at 7q11.2, the most consistent change detected, was confirmed by quantitative PCR. Poor correlation between the presence of tri-/tetrasomy and overexpression was observed for chromosomes 14 and 17. Two cases were reanalyzed versus (i) B cells, (ii) transformed B cells, and (iii) CD34+19+ cells (the putative counterpart of the leukemic cell). A reduction in the number of relatively overexpressed regions was observed with CD34+19+ cells. In particular, the peak at 7q11.2 disappeared, suggesting up-regulation of genes from this region in the early ontology of normal B-cell development. In conclusion, we have shown that tri-/tetrasomies in hyperdiploid ALL lead to an increase in the expression of associated sequences. The choice of a biologically relevant reference is crucial for data interpretation. © 2004 Wiley-Liss, Inc. [source] AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignanciesGENES, CHROMOSOMES AND CANCER, Issue 1 2003Takeshi Taketani AML1/RUNX1, located on chromosome band 21q22, is one of the most important hematopoietic transcription factors. AML1 is frequently affected in leukemia and myelodysplastic syndrome with 21q22 translocations. Recently, AML1 mutations were found in adult hematologic malignancies, especially acute myeloid leukemia (AML),M0 or leukemia with acquired trisomy 21, and familial platelet disorder with a predisposition toward AML. Through the use of polymerase chain reaction,single-strand conformation polymorphism analysis, we examined the AML1 gene for mutations in 241 patients with pediatric hematologic malignancies, and we detected AML1 mutations in seven patients (2.9%). Deletion was found in one patient, and point mutations in four patients, including three missense mutations, two silent mutations, and one mutation within an intron resulting in an abnormal splice acceptor site. All of the mutations except for one were heterozygous. Mutations within the runt domain were found in six of seven patients. Six of seven patients with AML1 mutations were diagnosed with AML, and one had acute lymphoblastic leukemia. In three of these seven patients, AML evolved from other hematologic disorders. AML1 mutations were found in two of four AML-M0 and two of three patients with acquired trisomy 21. Patients with AML1 mutations tended to be older children. Three of four patients with AML1 mutations who received stem cell transplantation (SCT) are alive, whereas the remaining three patients with mutations without SCT died. These results suggest that AML1 mutations in pediatric hematologic malignancies are infrequent, but are possibly related to AML-M0, acquired trisomy 21, and leukemic transformation. These patients may have a poor clinical outcome. © 2003 Wiley-Liss, Inc. [source] LAF4, an AF4 -related gene, is fused to MLL in infant acute lymphoblastic leukemiaGENES, CHROMOSOMES AND CANCER, Issue 1 2002Anne R.M. von Bergh Infant acute lymphoblastic leukemia (ALL) with MLL gene rearrangements is characterized by a proB phenotype and a poor clinical outcome. We analyzed an infant proB ALL with t(2;11)(p15;p14) and an MLL rearrangement on Southern blot analysis. Rapid amplification of cDNA ends,polymerase chain reaction (PCR) and reverse transcriptase-PCR identified the LAF4 gene mapped on chromosome region 2q11.2,q12 as a fusion partner of the MLL gene. The LAF4 gene was identified previously by its high sequence homology to the AF4 protein and encodes a protein of 1,227 amino acids. The t(4;11)(q21;q23), creating the MLL - AF4 chimeric transcripts, is the predominant 11q23 chromosome translocation in infant ALL and is associated with an extremely poor prognosis. Our findings further suggest that fusion of MLL to one of the AF4 family members (AF4/LAF4/AF5Q31) might determine a proB-cell phenotype in infant leukemia. © 2002 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||