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Biomedical subjects

E Macintyre

Publications and source records attributed to E Macintyre.

At least 19 recordsLinked to original sources
PubMed2006

Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study.

Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

Adolescent↗
PubMed2006

The MLL recombinome of acute leukemias.

Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.

Acute Disease↗
PubMed2006

Prediction of relapse by day 100 BCR-ABL quantification after allogeneic stem cell transplantation for chronic myeloid leukemia.

Chronic myeloid leukemia (CML) relapse after allogeneic stem cell transplantation (SCT) is a relatively frequent situation, which is correlated to disease status, time from diagnosis to transplant and T-cell depletion. We evaluated the potential for early minimal residual disease (MRD) BCR-ABL quantification to predict relapse of CML patients receiving allogeneic SCT. Minimal residual disease was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) at day 100 (d100) in 38 patients with >1 year follow-up after conventional non-T-cell-depleted SCT. Normal ABL control values from 1724 follow-up blood samples were used to define an RQ-PCR amplifiability index and the limits of reliable use of BCR-ABL ratios. We then compared the 14 patients with a high-level d100 BCR-ABL/ABL ratio (> or = 10(-4)) to that of the 24 patients with a negative/low-level ratio (<10(-4)). Despite being comparable for all classical parameters, the incidence of relapse was significantly higher in the high MRD group (11/14 (79%)) compared to that of the low/negative MRD group (7/24 (29%)) (P = 0.009), with d100 MRD values representing an independent risk factor of relapse and disease-free survival, but not of overall survival, in multivariate analysis. These data should facilitate risk-adapted post-transplant immunosuppression and/or tyrosine kinase inhibitor therapy based on an early evaluation of MRD.

Adolescent↗
PubMed2005

DEK-CAN molecular monitoring of myeloid malignancies could aid therapeutic stratification.

The t(6;9)(p23;q34) is a recurrent chromosomal abnormality observed in 1% of acute myelogenous leukemia (AML), which generates a fusion transcript between DEK and CAN/NUP214 genes. We used a DEK-CAN real-time quantitative (RQ)-PCR strategy to analyze 79 retrospective and prospective samples from 12 patients. Five patients reached DEK-CAN negativity (sensitivity 10(-5)); all underwent early allogeneic hematopoietic stem cell transplantation (median 5.5 months from diagnosis) with some demonstrating molecular positivity at the time of allograft. All four cases in CCR with adequate follow-up (median 18.5 months, range 13--95) demonstrate persistent molecular negativity, whereas all seven patients with persistent DEK-CAN positivity died at a median of 12 months from diagnosis (range 7--27). We conclude that DEK-CAN molecular monitoring by RQ-PCR in t(6;9) malignancies is a useful tool for individual patient management and that molecular negativity is indispensable for survival, but should not be a prerequisite for allografting in this rare, poor prognosis, subset of AML.

Adolescent↗
PubMed2004

IgH DJ rearrangements within T-ALL correlate with cCD79a expression, an immature/TCRgammadelta phenotype and absence of IL7Ralpha/CD127 expression.

cCD79a and IgH VDJ/DJ rearrangements are considered to be relatively specific for B lymphoid precursors. We looked for both in cCD3+, CD7+, CD19- T-ALLs classified by TCR status into alphabeta or gammadelta/immature (IM) lineages, with individualization of HOX11L2+ T-ALLs since they represent an intermediate alphabeta/gammadelta category. cCD79a was expressed at low levels in 47% of T-ALL and was most frequent in IMgamma T-ALLs. IgH rearrangements were common in gammadelta/IM (45%) and HOX11L2+ (35%) T-ALLs compared to HOX11L2-negative cases (3%; P<0.001). CD127 (IL7Ralpha) expression was also more common in the gammadelta/IM lineage but its expression was virtually mutually exclusive of IgH rearrangement. Low-level cCD79a expression alone should therefore not be interpreted as evidence of B lineage affiliation in immature leukemias. gammadelta/IM lineage T-ALLs potentially include two distinct categories: predominantly IgH+, cCD79a+, CD127- cases which retain gammadelta and B lymphoid potential and IgH-, cCD79a-, CD127+ cases with restricted T lineage potential.

Antigens, CD↗
PubMed2003

LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Adaptor Proteins, Signal Transducing↗
PubMed2003

[Application of molecular biology techniques to malignant haematology].

Malignant hemopathies, although heterogeneous in their prognosis and oncogenesis, represent an interesting model for studying cancer genesis mechanisms in man through the recurrent presence of genetic abnormalities involved in oncogenesis and the availability of tumour material. Nowadays, molecular biology techniques are very much used for the diagnosis, the treatment and the follow-up of these diseases. Firstly used for research, the new techniques have completely changed our ability to characterise malignant hemopathies and to understand the cancer-inducing processes, permitting us to perform the biological assessment of patients with malignant hemopathies, the diagnosis, and to estimate and follow the outcome of patients after treatment. At a more fundamental level, the structural and functional analysis of the deregulated genes implied in leukaemia and lymphoma has improved our knowledge and understanding of oncogenic and physiologic mechanisms significantly.

Biomarkers, Tumor↗
PubMed2003

Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) - a Europe against cancer program.

Real-time quantitative RT-PCR (RQ-PCR) is a sensitive tool to monitor minimal residual disease (MRD) in leukemic patients through the amplification of a fusion gene (FG) transcript. In order to correct variations in RNA quality and quantity and to calculate the sensitivity of each measurement, a control gene (CG) transcript should be amplified in parallel to the FG transcript. To identify suitable CGs, a study group within the Europe Against Cancer (EAC) program initially focused on 14 potential CGs using a standardized RQ-PCR protocol. Based on the absence of pseudogenes and the level and stability of the CG expression, three genes were finally selected: Abelson (ABL), beta-2-microglobulin (B2M), and beta-glucuronidase (GUS). A multicenter prospective study on normal (n=126) and diagnostic leukemic (n=184) samples processed the same day has established reference values for the CG expression. A multicenter retrospective study on over 250 acute and chronic leukemia samples obtained at diagnosis and with an identified FG transcript confirmed that the three CGs had a stable expression in the different types of samples. However, only ABL gene transcript expression did not differ significantly between normal and leukemic samples at diagnosis. We therefore propose to use the ABL gene as CG for RQ-PCR-based diagnosis and MRD detection in leukemic patients. Overall, these data are not only eligible for quantification of fusion gene transcripts, but also for the quantification of aberrantly expressed genes.

Archives↗
PubMed2003

Refractory coeliac sprue is a diffuse gastrointestinal disease.

BACKGROUND: Refractory coeliac sprue (RCS) with an immunophenotypically aberrant clonal intraepithelial lymphocyte (IEL) population is considered a cryptic form of intestinal T cell lymphoma. AIMS: To investigate the distribution of the abnormal and monoclonal IEL population in the digestive tract of RCS patients. PATIENTS AND METHODS: We compared the frequency of lymphocytic gastritis (LG) and lymphocytic colitis (LC), together with IEL phenotype and T cell clonality, in gastric and colonic samples from 15 adults with RCS (all with aberrant CD3 intracytoplasmic(+) surface(-) CD8(-) clonal IELs on duodenojejunal biopsies), 18 patients with active coeliac disease (ACD), and 10 patients with coeliac disease (CD) on a gluten free diet (GFD-CD) by means of immunohistochemistry and multiplex polymerase chain reaction amplification of the T cell receptor gamma gene (TCR-gamma) rearrangement. Blood samples of nine RCS patients were also tested for clonality. RESULTS: LG was found in 9/14 (64%), 11/18 (61%), and 3/10 (30%) patients with RCS, ACD, and GFD-CD, respectively, while LC was found in 6/11 (55%), 3/4 (75%), and 2/3 (66%) patients. Contrary to CD, all samples from patients with LG and LC showed an aberrant IEL phenotype. Monoclonal TCR-gamma rearrangements were detected in 8/13 (62%), 8/10 (80%), and 4/9 (44%) of gastric, colonic, and blood samples, respectively, from RCS patients, while in CD patients such rearrangements were only found in 2/25 (8%) gastric samples. CONCLUSION: The immunophenotypically aberrant monoclonal IEL population present in the small intestine of patients with RCS frequently disseminates to the blood and the entire gastrointestinal epithelium, suggesting that this is a diffuse gastrointestinal disease.

Adult↗
PubMed2002

Angio-immunoblastic T cell lymphoma (AILD-TL) rich in large B cells and associated with Epstein-Barr virus infection. A different subtype of AILD-TL?

We studied eight patients with characteristic features of angio-immunoblastic T cell lymphoma (AILD-TL) associated with more than 25% of large B cells. Polymerase chain reaction (PCR) analysis showed a clonal rearrangement of the T cell receptor (TCR)-gamma chain gene in all cases. One additional case showed a clonal rearrangement of the TCR-beta chain gene by Southern blot hybridization. PCR analysis showed a clonal immunoglobulin rearrangement in three cases presenting with more than 50% of large B cells whereas the other cases had a germline configuration. In 6/8 cases, double-labeling immunohistochemistry and in situ hybridization demonstrated that Epstein-Barr virus (EBV) was mostly present in the large B cells but also detected in some T cells. We further evaluated the frequency of AILD-TL with more than 25% of large B cells in the 106 cases collected by the French GELA group and found an incidence of 18%. The outcome of these patients did not differ significantly from those with less than 25% of B cells. With this approach we confirm the heterogeneity of AILD-TL features and the possible association with a substantial numbers of CD20(+), EBV(+) large B cells. We propose to denominate these cases as 'AILD-TL rich in large B cells' and to consider them as a different entity which can be misdiagnosed as a reactive process or as T cell rich B cell lymphoma.

Aged↗
PubMed2002

Typical essential thrombocythaemia does not express bcr-abelson fusion transcript.

Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder (MPD) characterized by an elevated platelet count and no identifiable underlying primary cause. According to the diagnostic criteria of the Polycythemia Vera Study Group (PVSG), ET lacks features diagnostic for other MPDs, including the Philadelphia chromosome (Ph) or bcr-abl rearrangement. Recently, some authors have reported bcr-abl transcript positivity in ET patients, but these findings remain controversial. The aim of this study was to investigate whether the bcr-abl transcript could be found in ET patients and to verify the hypothesis of a new ET variant. ET patients (n = 121) with a median age at diagnosis of 55 years were enrolled. The bcr-abl transcript status was examined by multiplex reverse transcription-polymerase chain reaction. Only two cases were positive for bcr-abl, one of which had the Ph at diagnosis. The positive bcr-abl transcript was associated, in both cases, with mild basophilia at diagnosis. After a median follow-up of 43 months (0-309 months), two patients in the bcr-abl-negative group developed Ph and bcr-abl-negative acute myeloid leukaemia (AML). In contrast, one of the two patients in the bcr-abl-positive group died from AML 13 years after diagnosis. In conclusion, our data on a large group of patients shows the rarity of the bcr-abl transcript in well-established ET. However, a subset of patients with apparent ET and basophilia may express the transcript and may constitute a novel entity intermediate between chronic myeloid leukaemia (CML) and typical ET. A prospective study is warranted in order to define better the clinical and biological characteristics of bcr-abl-expressing ET.

Adolescent↗
PubMed2000

High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21.

The AML1 gene, situated in 21q22, is often rearranged in acute leukemias through t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gene have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 patients, including 131 with acute myeloid leukemia (AML), 94 with myelodysplastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 with essential thrombocythemia (ET). Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 in 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chromosome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acquired trisomy 21 (1 M1AML, 2 M2AML, 1 ET, and 1 atypical CML). In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had the same missense or stop codon mutation in both AML1 alleles, which resulted in at least 3 of the patients having duplication of the mutated allele and deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagnosis and remission samples. In the remaining mutated cases, with acquired trisomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutations were acquired in the leukemic clone. In conclusion, these findings confirm the possibility of mutations of the Runt domain of the AML1 gene in leukemias, mainly in MoAML and in myeloid malignancies with acquired trisomy 21. AML1 mutations, in MoAML, involved both alleles and probably lead to nonfunctional AML1 protein. As AML1 protein regulates the expression of the myeloperoxidase gene, the relationship between AML1 mutations and Mo phenotype in AML will have to be further explored. (Blood. 2000;96:2862-2869)

Acute Disease↗
PubMed2000

The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype.

B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) are increasingly treated on risk-adapted protocols based on presenting clinical and biological features. Residual molecular positivity of clonal immunoglobulin (IG) and T-cell receptor (TCR) rearrangements allows detection of patients at an increased risk of relapse. If these rearrangements are to be used for universal follow-up, it is important to determine the extent to which they are informative in different BCP-ALL subsets. We show that IGH V-D-J rearrangements occur in 89% of 163 BCP-ALL, with no significant variation according to age or genotype (BCR-ABL, TEL-AML1, MLL-AF4, and E2A-PBX1). In contrast, TCRG rearrangements, which occur in 60% of patients overall, are frequent in BCR-ABL and TEL-AML1, are less so in MLL-AF4, and are virtually absent in infants aged predominantly from 1 to 2 years and in E2A-PBX1 ALLs. Incidence of the predominant TCRD Vdelta2-Ddelta3 rearrangement decreases with age but is independent of genotype. These differences are not due to differential recombination activating gene activity, nor can they be explained adequately by stage of maturation arrest. Analysis of MLL-AF4 BCP-ALL is in keeping with transformation of a precursor at an early stage of ontogenic development, despite the adult onset of the cases analyzed. We postulate that the complete absence of TCRG rearrangement in E2A-PBX1 cases may result from deregulated E2A function. These data also have practical consequences for the use of TCR clonality for the molecular follow-up of BCP-ALL.

Adolescent↗