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Biomedical subjects

G Mitterbauer

Publications and source records attributed to G Mitterbauer.

At least 19 recordsLinked to original sources
PubMed2005

The impact of prolonged strenuous endurance exercise on interleukin 18 and interleukin 18 binding protein in recreational cyclists.

Interleukin 18 (IL-18) is an important pro-inflammatory cytokine in the early phase of human immune response to microbial infections. The influence of strenuous exercise on the intrinsic balance of IL-18 and its endogenous antagonist IL-18 binding protein (IL-18 BP) is unknown, but could be of major relevance for the athlete's immune function empirically and epidemiologically proven to be altered after exhaustive exertion. To study the effect of strenuous marathon cycling on the interaction of IL-18 and IL-18 BP we investigated 37 male, healthy, and well-trained amateur cyclists participating in the Otztaler Radmarathon in Tyrol (distance: 230 km; cumulative altitude difference: 5500 m). IL-18 was measured by a commercially available ELISA-Kit and IL-18 BP by a novel IL-18 BP ELISA method. Free, unbound IL-18 was calculated according to a standard equation. The mean plasma level of IL-18 was 142.27 +/- 21.85 pg/ml pre-race, remained nearly unchanged (124.35 +/- 13.16 pg/ml; p = 1.0) immediately after competition (mean race time 9 h 38 min), but declined significantly 24 h afterward (62.92 +/- 6.80 pg/ml; p = 0.002). The plasma levels of IL-18 BP increased considerably immediately after and kept on rising for the following 24 h (pre-race: 1.51 +/- 0.20 ng/ml; immediately post-race: 3.84 +/- 0.26 ng/ml, p < 0.001; 24 h post-race: 4.33 +/- 0.42 ng/ml, p < 0.001). Therefore, the calculated free IL-18 was 122.06 +/- 16.79 pg/ml pre-race, declined to 82.86 +/- 8.59 (p = 0.05) immediately post-race and to 39.17 +/- 3.76 pg/ml 24 h post-race (p < 0.001). The respective percentages of this post-exercise reduction in free IL-18 plasma levels were 32 % and 68 %. The present study reveals an exercise-induced significant decline in free IL-18 accompanied by an immediate up-regulation of IL-18 BP and decreased IL-18 in marathon cyclists. This down-regulation of free IL-18 may (i) limit the magnitude and duration of a too excessive inflammatory response to the exercise-induced tissue damage and (ii) on the other hand contribute to the elevated susceptibility to infection in athletes undergoing exhaustive exercise.

Adult↗
PubMed2004

Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse.

Karyotype is an important prognostic factor in patients with newly diagnosed acute myeloblastic leukaemia (AML). The prognostic value of cytogenetics on the outcome of patients with AML in relapse has not yet been well defined. We analysed the clinical outcome of 152 patients with de novo, chemotherapy-treated AML in first relapse according to the cytogenetic classification of the United Kingdom Medical Research Council. The rate of second complete remission (CR) (88, 64 and 36%) and the probability of survival at 3 years (43, 18 and 0%) were significantly different between the favourable, intermediate and adverse cytogenetic risk groups, respectively. Compared to the favourable group, the relative risk (RR) of death (multivariate analyses) was 2.6 (confidence interval (CI): 1.5-4.4, P<0.001) for the intermediate and 3.7 (CI: 1.7-7.9, P=0.001) for the adverse group. The prognostic value of the duration of first CR was confirmed (RR of death: 2.0 (CI: 1.0-4.0) for each additional year in first CR), whereas the FLT3 mutation obtained at diagnosis did not markedly influence the outcome of patients with AML in relapse. In conclusion, our results indicate that both karyotype and the duration of first CR are independent prognostic factors for patients with de novo AML in first relapse.

Acute Disease↗
PubMed2004

Effect of ultramarathon cycling on the heart rate in elite cyclists.

OBJECTIVES: To analyse the heart rate (HR) response and estimate the ultraendurance threshold-the optimum maintainable exercise intensity of ultraendurance cycling-in ultraendurance elite cyclists competing in the Race across the Alps. METHODS: HR monitoring was performed in 10 male elite cyclists during the first Race across the Alps in 2001 (distance: 525 km; cumulative altitude difference: 12 600 m) to investigate the exercise intensity of a cycle ultramarathon and the cardiopulmonary strains involved. Four different exercise intensities were defined as percentages of maximal HR (HR(max)) as follows: recovery HR (HR(re)), <70% of HR(max); moderate aerobic HR (HR(ma)), 70-80%; intense aerobic HR (HR(ia)), 80-90%; and high intensity HR (HR(hi)), >90%. RESULTS: All athletes investigated finished the competition. The mean racing time was 27 hours and 25 minutes, and the average speed was 18.6 km/h. The mean HR(max) was 186 beats/min, and the average value of measured HRs (HR(average)) was 126 beats/min resulting in a mean HR(average)/HR(max) ratio of 0.68, which probably corresponds to the ultraendurance threshold. The athletes spent 53% (14 hours 32 minutes) of total race time within HR(re), 25% (6 hours 51 minutes) within HR(ma), 19% (5 hours 13 minutes) within HR(ia), and only 3% (49 minutes) within HR(hi), which shows the exercise intensity to be predominantly moderate (HR(re) + HR(ma) = 78% or 21 hours 23 minutes). The HR response was influenced by the course profile as well as the duration. In all subjects, exercise intensity declined significantly during the race, as indicated by a decrease in HR(average)/HR(max) of 23% from 0.86 at the start to 0.66 at the end. CONCLUSIONS: A substantial decrease (10% every 10 hours) in the HR response is a general cardiovascular feature of ultramarathon cycling, suggesting that the ultraendurance threshold lies at about 70% of HR(max) in elite ultramarathon cyclists.

Adult↗
PubMed2003

The effect of marathon cycling on renal function.

The stress of strenuous long-term exercise may alter renal function. Whether this is also true for marathon cycling is unknown so far. The purpose of this study was to evaluate renal function following competitive marathon cycling. We investigated 38-male, well-trained recreational cyclists credibly not taking any kind of doping who participated in the Otztal Radmarathon. Blood and urine specimens were taken the day before, immediately after and one day after competition. Baseline renal functional parameters--normal before competition--increased significantly afterwards and remained elevated during 24 hours of recovery. The rises in serum creatinine, urea and uric acid were 20, 54 and 42 % (p < 0.001 respectively). The corresponding decline in estimated creatinine clearance was 18 %. In all athletes the serum urea/creatinine ratio rose above 40, fractional sodium excretion and fractional uric acid excretion fell below 0.4 % and 15 %, indicating reduced renal perfusion. The observed effects lasted for at least 24 h despite a stable fluid balance during the race and an expanding plasma volume (PV) in the recovery period. Levels of haematocrit remained unchanged immediately post-race but significantly declined from 0.44 to 0.41 on the following day (p < 0.001). The calculated rise in PV was + 10.8 %. Electrolyte homeostasis was preserved throughout the observation period. Post-exercise proteinuria was small and of the mixed glomerular-tubular type. There was neither evidence for exercise-induced haemolysis, nor for significant skeletal muscle damage. The finding obtained from well-hydrated recreational athletes reveals that the extraordinary strains of marathon cycling influence renal function only on a minimal scale. Though minor, the physiological effects were long-lasting. The results obtained suggest that a reduced renal perfusion is the mechanism responsible for the slight impairment of renal function following exhaustive marathon cycling.

Adult↗
PubMed2003

Heart rate response to ultraendurance cycling.

The heart rate (HR) response to ultraendurance cycling is poorly understood. This case report describes the exercise intensity of ultraendurance cycling by means of HR monitoring in a well trained male amateur cyclist performing the Otztal Radmarathon twice en bloque in a circuit of two identical laps (distance 460 km; cumulative altitude difference 11,000 m). The overall intensity was moderate (HR(mean) = 130 beats/min; HR(mean)/HR(max) = 0.71) corresponding to an average individual workload of 47% of VO(2)MAX. Almost the whole race was performed under aerobic conditions (99.6%); high intensity work was negligible (0.4%). The average speed and the HR response also declined in the course of the two laps, average speed by 17.2% (23.8 to 19.7 km/h), HR(mean) by 10.1% (138 to 124 beats/min), and HR(mean)/HR(max) by 10.7% (0.75 to 0.67). This scale of HR decrease corresponds to comparable data gained in the field of triathlon and represents a specific cardiac feature of ultraendurance exercise in general.

Adult↗
PubMed2002

A comparative study on demographic, hematological, and cytogenetic findings and prognosis in acute myeloid leukemia with and without leukemia cutis.

We studied the incidence of leukemia cutis (LC) in 381 consecutive patients with acute myeloid leukemia (AML) in a single institution and compared the demographic, hematological, and cytogenetic findings in AML patients with and without LC. We also examined the response to intensive chemotherapy, overall survival, and duration of remission in this patient population with regard to the presence of LC. The prevalence of LC was 3.7% in clinically diagnosed patients and 2.9% in biopsy-proven cases, respectively. Patients with and without LC did not differ with regard to age, sex, white blood cell counts, hemoglobin, fibrinogen, and platelet counts at diagnosis, but lactate dehydrogenase (LDH) was significantly higher in patients with LC. Various karyotype abnormalities were found, but in patients with LC numerical abnormalities of chromosome 8 were significantly more common ( P<0.0001). Patients with LC did not differ from patients without LC with regard to remission rate, but there was a trend towards shorter remission duration in patients with LC. We conclude that patients with LC have some features different from patients without this symptom. The increased frequency of numerical aberrations of chromosome 8 in patients with LC was the most interesting observation of our study. The pathophysiological significance of this finding remains to be determined.

Adult↗
PubMed2002

Alternative end-joining in follicular lymphomas' t(14;18) translocation.

T(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between the BCL2 proto-oncogene and the IGH locus during the D(H) to J(H) joining phase of V(D)J recombination in early B cells. Analysis of the breakpoint junctions suggests that translocation derives from the fusion between normal V(D)J recombination intermediates at the IGH locus and non-V(D)J-mediated broken-ends at the BCL2 locus. So far, BCL2 broken-ends have only been observed fused to coding-ends, raising questions concerning the molecular constraints of the illegitimate joining process. Using a combination of genome walking and long-range PCR assays, we describe in this report that in 4.5% (2/44) of the t(14;18), one of the BCL2 broken-ends is fused to a signal-end. The formation of these J(H)RSS/BCL2 junctions provides direct evidence that BCL2 broken-ends are capable of joining to both products of V(D)J recombination, suggesting their presence in the RAG-mediated post-cleavage complex. In addition, junctions generated by this alternative end-joining do not involve deletion of the chromosome 14 intervening sequences generally lost in the standard translocation, providing a unique opportunity to investigate the rearrangement status of this region in the translocated IGH allele. In both cases, a DJ(H) rearrangement could be detected 5' of the J(H)-RSS/BCL2 junction. These findings, together with the previously reported bias towards the most external D(H) and J(H) segments in standard breakpoints, strongly suggest that t(14;18) preferentially occurs during an attempted secondary D(H) to J(H) rearrangement. This unusual and restricted window of differentiation opens intriguing questions concerning the etiology of the translocation.

Base Sequence↗
PubMed2002

Short-term effects of prolonged strenuous endurance exercise on the level of haematocrit in amateur cyclists.

Knowledge is sparse about the extent of potential dehydration due to prolonged strenuous cycling and its haematological acute effects on the haematocrit (Hct) in study populations credibly not taking any kind of doping. With increasing training load levels of Hct and haemoglobin (Hb) decrease in both amateurs and professionals as a long-term consequence due to expanded plasma volume (PV). On a short-term basis, however, counteracting dehydration potentially brought about by endurance exercise may cause a rise in Hct bringing competitive cyclists into conflict with the current condition regulations and Hct cut-off of 50 % set by the International Cycling Union (UCI) in its fight against erythropoietin (rhEPO) doping. On the other hand adequate and sufficient fluid substitution being substantial for a successful endurance performance should prevent any pronounced Hct rises. To study the haematological acute effects of prolonged strenuous cycling we measured Hct, Hb, red blood cell (RBC) count and plasma protein in a reliably 'clean' population of 38 well-trained male amateur cyclists before, immediately after and one day after an extraordinary ultramarathon. The pre-race levels of Hct, Hb and RBC count were placed in the lower range of normal distribution and well below the Hct cut-off limit of the UCI. Immediately post-exercise the mean levels of Hct, Hb, RBC count and protein remained unchanged. One day after race, however, all four parameters significantly dropped by 3 %, 6.7 %, 6.5 %, 9.9 % respectively (p < 0.001), indicating marked post-exercise PV expansion. The calculated percentage increase in PV was 11.9 %. No evidence for coexisting exercise-induced haemolysis was found. Our study shows that in "clean, rhEPO-free" amateur cyclists who involve in strenuous marathon cycling the haematological short-term effects of extraordinary marathon cycling consist in considerable PV expansion making Hct values fall on the following day. The findings - gained from amateurs though - suggest that despite all its disadvantages the UCI Hct cut-off represents an appropriate means to discourage from excessive rhEPO doping at least as long as the available direct methods for detecting this kind of misuse are not yet applied by the international sports federations.

Adult↗
PubMed2002

Exercise intensity of cycle-touring events.

The aim of the study was to analyze the exercise intensity of recreational cyclists participating in a cycling-touring event. In 14 male healthy recreational cyclists heart rate (HR) monitoring was performed during the Otztal Radmarathon 1999 (distance: 230 km; altitude difference: 5500 m) in order to evaluate the HR response and to estimate the cardiopulmonary strains for the less-trained athlete confronted with such a marathon. Four different exercise intensities were defined as percentages of maximal HR (HR(max)) as follows: recovery HR (HR(re)) < 70 % of HR max; moderate aerobic HR (HR(ma)) = 70 - 80 %; intense aerobic HR (HR(ia)) = 80 - 90 %; and anaerobic HR (HR(an)) > 90 %. All athletes finished the competition successfully. The mean racing time was 10 h 14 min, the average speed 22.5 km/h. The mean HR(max) was 188 bpm, the average value of the measured HRs (HR(average)) was 145 bpm resulting in a mean HR(average)/HR(max) ratio of 0.77. Athletes spent 18.5 % (1 h 54 min) of total race time within HR(re), 28 % (2 h 52 min) within HR(ma), 39.5 % (4 h 02 min) within HR(ia), and 14 % (1 h 26 min) within HR(an). The vast majority of exercise was done under "aerobic conditions" (HR(re) + HR(ma) + HR(ia) = 86 % or 8 h 48 min) - confirming the knowledge that the aerobic energy supply is crucial for the performance of long-term exercise. The large amount of high exercise intensities (HR(ia) + HR(an) = 53.5 % or 5 h 30 min), however, features the intense cardiopulmonary strains evoked by such competitions. The HR response was related to the course profile with HRs significantly declining in all subjects to an extent of 10 % during the course of race. Our findings show that the exercise intensity borne by recreational cyclists during a cycle-touring event is high and very similar to that of professionals. With respect to the high cardiovascular strains a thorough medical screening is advisable for any participant of such an event combining both high volume and high intensity loads.

Adult↗
PubMed2002

Selection of autologous CD4+ T-cells for adoptive T-cell substitution in patients with CD23+ B-cell CLL.

BACKGROUND: B-cell CLL (B-CLL) is accompanied by a progressive decrease in cellular immune functions, and treatment-related immunosuppression can further aggravate T-cell immunodeficiency. To reduce the risks of T-cell depletion, it seems feasible to collect autologous CD4+ cells at an early disease stage and subsequently reinfuse them during periods of profound T-cell depletion. METHOD: We describe a two-step cell-selection method to obtain highly enriched CD4+ T-cells from leukapheresis compounds of patients with CD23+ B-CLL. The double selection procedure was performed using the CellPro Ceperate device, and consisted of CD4+ selection followed by CD23 purging to further remove contaminating CD23+ B-cells from the CD4+ cell fraction. The results of eight runs performed with leukapheresis material obtained from eight patients with CD23+ B-CLL at different disease stages are presented. RESULTS: The CD4/CD23 double cell-selection procedure resulted in the purification of > 90% CD4+ cells. Median recovery of CD4+ T lymphocytes after selection was 46%, and was negatively affected by the initial tumor cell load. The final T-cell fraction still contained lymphocytes of the B-CLL clone, as determined by FACS and PCR. The cell-processing procedure had no impact on T-cell function, as assessed by the in vitro production of the cytokine interferon-gamma. Moreover, the selected CD4+ cells retained their capacity to co-stimulate mitogen-induced B-cell IgG production in vitro. CONCLUSION: The described CD4 selection/CD23 depletion strategy is a suitable approach to obtaining high numbers of functional active autologous CD4+ T cells for adoptive T-cell transfer in patients with CD23+ BCLL.

Aged↗
PubMed2001

Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma.

The t(11;14)(q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (IgH) loci in mantle cell lymphoma (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14; 18) in follicular lymphoma (FL). We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BCL-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides; U. Jäger et al., Blood, 95: 3520-3529, 2000). Reasoning that the earlier (pregerminal center) B-cell origin of MCL might be reflected in a different molecular structure of the chromosomal breakpoints, we PCR-amplified diagnostic samples from 93 patients. Thirty-six samples (39%) were positive for the direct (BCL-1/J(H)) and 23 for both direct and reciprocal (D(H)/BCL-1) junctions. The breaks on chromosome 14 exhibited features of V(D)J-mediated recombination as shown by D(H) and J(H) coding end processing. However, duplications of BCL-1 sequences in 39% of the 23 patients indicate staggered double-strand breaks in the major translocation cluster region (MTC). This is incompatible with V(D)J recombination and indicates a different mechanism of cleavage. The use of J(H)6 in the junctions (39%) was similar to that in the immunoglobulin genes of normal B cells and B-CLL, but considerably less than in FL. Only 2 of 36 samples contained a BCL-1/DJ(H) rearrangement, which was indicative of a previous DJ(H) rearrangement. Most importantly, 19% of the BCL-1/IgH junctions with inserts of > or =5 nucleotides contained error-prone copies (T-nucleotides) of 8-12 nucleotides originating from the surrounding BCL-1 or IgH regions, a lower rate than in FL. No correlation was found between the addition of T-nucleotides and the rate of somatic mutation in the immunoglobulin genes. We conclude that the t(11;14) and t(14;18) use the same basic mechanism of translocation including V(D)J-mediated recombination, double-strand staggered breaks, and template-dependent, error-prone DNA-synthesis. However, the distinct differences in the utilization of J(H) regions suggest that the t(11;14) occurs predominantly during an attempted primary D(H)-J(H) rearrangement in early B cells, whereas the t(14;18) mostly occurs during secondary rearrangement. This is in agreement with the pregerminal center B-cell origin of MCL.

Base Sequence↗
PubMed2001

A case of 'smouldering' mastocytosis with high mast cell burden, monoclonal myeloid cells, and C-KIT mutation Asp-816-Val.

Mastocytosis is a term used for a group of disorders characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems. In patients with systemic mastocytosis (SM) the clinical course may be indolent or aggressive or even complicated by leukemic progression or an associated clonal hematologic non mast cell lineage disease (AHNMD). However, at first presentation (diagnosis) it may be difficult to define the category of disease and the prognosis. We report on a 48-year-old female patient with SM with urticaria pigmentosa-like skin lesions and mediator-related symptoms. She was found to have splenomegaly, a high infiltration grade (MC) in bone marrow biopsies (>30%), mild anemia, and a high serum tryptase level (>500 ng/ml). In addition, she exhibited discrete histologic signs of myeloproliferation in the 'non-affected' marrow and monoclonal blood cells established by C-KIT 2468A-->T mutation (Asp-816-Val) -analysis and HUMARA assay. Despite these findings, however, the clinical course was stable over years and no AHNMD or organ impairment developed. Because of the 'intermediate' clinical signs and absence of progression to aggressive disease, we proposed the term 'smouldering mastocytosis'.

Adult↗
PubMed2001

Long-term clinical and molecular remission after allogeneic stem cell transplantation (SCT) in patients with poor prognosis non-Hodgkin's lymphoma.

From 1987 to 1999 35 patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL-2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin's lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatment-related mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.

Adult↗
PubMed2001

PBPC mobilization with chemotherapy and G-CSF in patients with chronic myeloid leukemia: quantification of bcr/abl-positive cells by interphase fluorescence in situ hybridization and competitive PCR.

BACKGROUND: Autografting of normal stem cells mobilized after chemotherapy is increasingly used in chronic myeloid leukemia (CML). Thus, quantification of possible contamination of progenitor cell apheresis with breakpoint cluster region (bcr)/Abelson murine leukemia (abl)-positive cells is of great clinical interest. STUDY DESIGN AND METHODS: Two molecular methods were compared to quantify bcr/abl positivity in leukapheresis components obtained after mobilizing chemotherapy in six patients with CML. To document the efficacy of in vivo purging, the leukapheresis procedures were monitored with interphase fluorescence in situ hybridization (FISH) and quantitative competitive PCR (QC-PCR) as a ratio of bcr/abl:abl. RESULTS: From the first to the last leukapheresis, bcr/abl positivity in FISH increased from a median of 11 percent to 33 percent. For bcr/abl transcripts, a simultaneous increase in consecutive leukapheresis procedures was seen. The median percentage of bcr cells in a bcr/abl:abl ratio was 3.1 percent in the first apheresis. In the last apheresis after the mobilization with mRNA, the QC-PCR showed a median of 19.5 percent. FISH and QC-PCR showed a statistical significant increase of bcr/abl positivity from the first to the last apheresis. CONCLUSIONS: Both FISH and QC-PCR were reliable methods of quantifying bcr/abl positivity, and they allowed selection of the optimal apheresis component for autologous transplantation. In both methods, a significant increase in bcr/abl positivity was seen from the first to the last leukapheresis. With FISH, results can be obtained within 24 hours. This method may prevent additional contaminated leukapheresis in case of increasing percentages of bcr/abl-positive cells.

Adult↗
PubMed2000

Variant intra philadelphia translocation with rearrangement of BCR-ABL and ABL-BCR within the same chromosome in a patient with cALL.

A unique variant Philadelphia translocation accompanied by the loss of the short arm of chromosome 9 in a 32-year-old female with common acute lymphoblastic leukemia (cALL) is described. Furthermore, supernumerary chromosome 8 material was found as an insertion into the long arm of chromosome 2 and/or as ring chromosomes in addition to two normal chromosomes 8. The chromosomal abnormalities were identified by combined conventional chromosome banding analysis and fluorescence in situ hybridization (FISH). The BCR-ABL rearrangement was confirmed by FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) studies. Possible mechanisms leading to this variant intra Philadelphia translocation are discussed. The aberrations found have prognostic implications, because 9p anomalies confer an adverse effect to the already poor prognosis of Philadelphia-positive ALL.

Adult↗
PubMed2000

Follicular lymphomas' BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation.

The human t(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between BCL-2 and D(H)/J(H) gene segments during V(D)J recombination in early B cells. De novo nucleotides are found inserted in most breakpoints and have been thus far interpreted as nontemplated N region additions. In this report, we have analyzed both direct (BCL-2/J(H)) and reciprocal (D(H)/BCL-2) breakpoints derived from 40 patients with follicular lymphoma with t(14;18). Surprisingly, we found that more than 30% of the breakpoint junctions contain a novel type of templated nucleotide insertions, consisting of short copies of the surrounding BCL-2, D(H), and J(H) sequences. The features of these templated nucleotides, including multiplicity of copies for 1 template and the occurrence of mismatches in the copies, suggest the presence of a short-patch DNA synthesis, templated and error-prone. In addition, our analysis clearly shows that t(14;18) occurs during a very restricted window of B-cell differentiation and involves 2 distinct mechanisms: V(D)J recombination, mediating the breaks on chromosome 14 during an attempted secondary D(H) to J(H) rearrangement, and an additional unidentified mechanism creating the initial breaks on chromosome 18. Altogether, these data suggest that the t(14;18) translocation is a more complex process than previously thought, involving the interaction and/or subversion of V(D)J recombination with multiple enzymatic machineries.

Base Sequence↗
PubMed2000

The "typical" immunophenotype of acute promyelocytic leukemia (APL-M3): does it prove true for the M3-variant?

The immunophenotypes of 12 acute promyelocytic leukemias (APL-M3; eight hypergranular, four microgranular) with documented PML-RAR-alpha fusion gene are presented. Bone marrow mononuclear cells were immunophenotyped using a panel of 20 monoclonal antibodies. The hypergranular APLs exhibited a mature myeloid phenotype as it has been described to be typical for M3. No lineage infidelity was detectable in classic M3 cases. In contrast, among the four cases of M3 variant, all leukemias showed marked expression of CD34 and two of four cases expressed the HLA-DR antigen. The CD2 antigen was expressed in three of four cases. Furthermore, one case showed expression of the CD56 antigen, and one case was positive for the blood group H antigen. The data suggest that microgranular APL is a heterogeneous entity with regard to the immunologic phenotype.

Adult↗