National Cancer Institute®
Last Modified: September 1, 2002
UI - 12130511
AU - Tafuri A; Gregorj C; Petrucci MT; Ricciardi MR; Mancini M; Cimino G;
TI - Mecucci C; Tedeschi A; Fioritoni G; Ferrara F; Di Raimondo F; Gallo E; Liso V; Fabbiano F; Cascavilla N; Pizzolo G; Camera A; Pane F; Lanza F; Cilloni D; Annino L; Vitale A; Vegna ML; Vignetti M; Foa R; Mandelli F; GIMEMA Group MDR1 protein expression is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia.
SO - Blood 2002 Aug 1;100(3):974-81
AD - Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza, Roma, Italy. firstname.lastname@example.org
Little is known about the prognostic role of multidrug resistance (MDR) in adults with newly diagnosed acute lymphoblastic leukemia (ALL). In the context of the GIMEMA ALL0496 protocol, we evaluated the impact of MDR1 (protein expression and function) on the achievement of complete remission (CR) and clinical outcome. Flow cytometric analysis of MDR1 expression (D) and function (rhodamine-123 efflux) was obtained in 203 and 158 patients, respectively. MDR1 expression was detected in 44 (21.7%) of 203 patients, and function was found in 23 (14.6%) of 158 (14.6%) patients. Expression of the multidrug resistance-associated protein 1 (MRP1) and lung-resistance protein (LRP) evaluated in 43 samples was found in 13 and 26 patients, respectively. Among the 200 patients evaluable for the clinical correlation study, 125 (79.6%) of 157 without MDR1 expression achieved CR compared with 23 (53.5%) of 43 with MDR1 expression (P =.001). At univariate analysis, MDR1 expression was significantly associated with CR when considered as a dichotomized (P =.001) or continuous (P =.01) variable. At multivariate analysis, dichotomized evaluation of MDR1 expression independently predicted CR (P =.004) with age (P =.03) and CD34 (P =.03); as a continuous variable, MDR1 expression (P =.03) was the only significant factor other than CD34 (P =.01). MDR1 function failed to predict achievement of CR or of MRP1 and LRP expression. MDR1 expression did not correlate with CR duration, nor did it predict for survival duration. These results demonstrate that MDR1 expression in de novo adult ALL is an independent predictor of CR achievement.
UI - 10025890
AU - Serrano J; Roman J; Jimenez A; Castillejo JA; Navarro JA; Sanchez J;
TI - Garcia-Castellanos JM; Martin C; Maldonado J; Torres A Genetic, phenotypic and clinical features of acute lymphoblastic leukemias expressing myeloperoxidase mRNA detected by RT-PCR.
SO - Leukemia 1999 Feb;13(2):175-80
AD - University Hospital Reina Sofia, Cordoba, Spain.
Myeloperoxidase (MPO) is found in the azurophilic granules of normal myelocytic cells. Cytochemical staining for MPO activity is used clinically to distinguish myeloid from acute lymphoid leukemias (ALL). However, using a highly sensitive RT-PCR technique, it is possible to detect MPO mRNA in otherwise clear ALL. The significance of this finding remains poorly understood. We have extended our observations to a series of 57 patients with the primary diagnosis of ALL (46 patients tested at diagnosis and 11 cases at relapse). We identified 25 cases (43.8%) of MPO mRNA(+)/enzyme(-) ALL (17 B cell and eight T cell lineage). Expression of myeloid antigens (CD13 or CD33) were detected in nine of them, and remarkably, 18 cases (72%) displayed CD34. Of these 25 MPO mRNA(+) leukemias, 10 (40%) are Bcr-Abl positive (with P210 fusion transcript in five patients while the five remaining cases carried P190 transcript). Moreover, 11 of 16 myeloid negative cases were also negative for any type of Bcr-Abl and MLL rearrangement, indicating that MPO mRNA positivity is not either invariably related to that chromosomal abnormality or necessarily associated with the presence of other myeloid differentiation features. Interestingly, six of these 11 cases are T-ALL, suggesting the presence of some overlapping phase for T and myeloid lineage commitment. Taken together, these findings could suggest a separate biological disease with immature origin and bipotential differentiation capability, which involves B and T-ALL subtypes and should lead to new investigations regarding their prognostic impact.
UI - 11154239
AU - Carter TL; Watt PM; Kumar R; Burton PR; Reaman GH; Sather HN; Baker DL;
TI - Kees UR Hemizygous p16(INK4A) deletion in pediatric acute lymphoblastic leukemia predicts independent risk of relapse.
SO - Blood 2001 Jan 15;97(2):572-4
AD - Division of Children's Leukaemia and Cancer Research, TVWT Institute for Child Health Research, University of Western Australia, West Perth.
The genes at the INK4A/ARF locus at 9p21 are frequently involved in human cancer. Virtually all p16(INK4A) exon 2 (henceforth called p16) inactivation in pediatric acute lymphoblastic leukemia (ALL) occurs by gene deletion. The results of this study illustrate that real-time quantitative polymerase chain reaction is capable of detecting gene deletion in primary patient specimens with a precision not previously achieved by conventional methods. Importantly, this assay includes the detection of hemizygous deletions. The study revealed, strikingly, that the risk ratio for relapse for hemizygous deletion compared with no deletion was 6.558 (P =.00687) and for homozygous deletion was 11.558 (P =.000539). These results confirm and extend the authors' previous findings that homozygous deletion of p16 in pediatric ALL patients is an independent prognostic indicator of outcome from therapy.
UI - 12150726
AU - Chen H; Wu S
TI - Hypermethylation of the p15(INK4B) gene in acute leukemia and myelodysplastic syndromes.
SO - Chin Med J (Engl) 2002 Jul;115(7):987-90
AD - Department of Hematology, First Hospital of Peking University, Beijing 100034, China.
OBJECTIVE: To detect the methylation pattern of the p15(INK4B) gene and to explore its significance in the pathogenesis of acute leukemia (AL) and leukemic transformation of myelodysplastic syndromes (MDS). METHODS: A total of 49 AL cases and 22 MDS cases were analyzed by methylation specific polymerase chain reaction (MSP) for methylation patterns in CpG islands of the p15(INK4B) gene. RESULTS: Hypermethylation of the p15(INK4B) gene was found in 90% (26/29) of newly diagnosed AL, including 46% with complete methylation and 54% with partial methylation. All 3 evolved AL from MDS and 9 relapsed AL showed a methylated p15(INK4B) gene and the proportion of complete methylation was 67% and 56% respectively. Only 5 of 11 (45%) AL in remission, including 2 in complete remission (CR) and 3 in partial remission (PR), were partially methylated. The frequency of p15(INK4B) gene methylation in newly diagnosed or relapsed AL was significantly higher than that in AL in the remission stage (P = 0.002) p15(INK4B) gene methylation was found in 5 of 13 (38%) low-risk MDS (RA/RAS) patients and 80% of them showed only partial methylation. However, p15(INK4B) gene methylation was found in all 9 cases in the high-risk group (RAEB/RAEB-T), including complete methylation in 56%, significantly different from the low-risk MDS group (P = 0.002). CONCLUSIONS: Hypermethylation of the p15(INK4B) gene occurs frequently in leukemia and high-risk MDS. It is possible that hypermethylation of this gene is related to the pathogenesis and development of AL and MDS. It may be used as a gene marker to detect minimal residual disease, relapse of AL and leukemic transformation in MDS.
UI - 11697497
AU - Firat H; Favier R; Adam M; Leverger G; Landman-Parker J; Cayre Y; Douay
TI - L Determination of myeloid antigen expression on childhood acute lymphoblastic leukaemia cells: discrepancies using different monoclonal antibody clones.
SO - Leuk Lymphoma 2001 Aug;42(4):675-82
AD - Service d'Hematologie Biologique, Hjpital d'enfants Armand Trousseau, Paris, France.
Prospective clinical studies including large numbers of patients have led to the conclusion that co-expression of myeloid antigens in childhood acute lymphoblastic leukaemia (My+ ALL) does not have prognostic significance. However, reports of the frequency of My+ ALL in children vary widely across laboratories using different mAb clones and staining and analysing procedures. Taking two commonly accepted thresholds of positivity for myeloid antigens (20 and 30%), we analysed the immunoreactivity of the most widely employed mAb clones against CD13 (SJ1D1, L138 and My7) and CD33 (My9, P67.6 and D3HL60) and compared the proportions of My+ ALL detected by these clones in childhood ALL. The correlation between myeloid antigen expression and the presence of the t(12;21) translocation was analysed concomitantly in the same samples. The percentage of ALL cases positive for myeloid markers varied significantly depending on the mAb clone and the positive threshold. Among patients with B-ALL, the proportion of CD13+ ALL was significantly lower using SJ1D1 than using L138 or My7, while the proportion of CD33+ ALL was significantly higher for My9 than for P67.6 or D3HL60. Analysis of the co-expression of CD13 and CD33 on B-ALL cells using combinations of mAb clones showed that this frequency was either underestimated by the SJ1D1/D3HL60 or overestimated by the L138/P67.6 and My7/My9 combinations. A correlation between CD13/CD33 positivity and the t(12;21) translocation was uniformly observed in B-ALL patients for a positive threshold of 30%, whereas SJ1D1/D3HL60 detected no correlation between t(12;21) and CD13/CD33 positivity when the threshold was lowered to 20%. These data show that the mAb clones commonly used to detect the CD13 and CD33 surface antigens have variable immunoreactivity against childhood ALL cells, which may partly explain the conflicting reports concerning the prognostic significance of myeloid antigen expression in paediatric ALL and its association with different translocations. The present findings may also be of clinical importance for therapeutic choices.
UI - 10515890
AU - Mori N; Nunokawa Y; Yamada Y; Ikeda S; Tomonaga M; Yamamoto N
TI - Expression of human inducible nitric oxide synthase gene in T-cell lines infected with human T-cell leukemia virus type-I and primary adult T-cell leukemia cells.
SO - Blood 1999 Oct 15;94(8):2862-70
AD - Department of Preventive Medicine and AIDS Research, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. email@example.com
We examined the expression of messenger RNA (mRNA) of the human inducible nitric oxide synthase (hiNOS) gene in a panel of human T-cell lines. Reverse transcriptase-polymerase chain reaction showed that human T-cell leukemia virus type-I (HTLV-I)-infected T-cell lines (MT-1, SLB-1, and C5/MJ) expressed mRNA for the hiNOS, but TL-Om1 or uninfected Jurkat, H9, and CCRF-CEM did not. The MT-1, SLB-1, and C5/MJ cell lines are infected with HTLV-I and express the viral transactivator Tax, whereas TL-Om1 cells, although derived from adult T-cell leukemia (ATL) leukemic cells, do not express Tax. There was, thus, a correlation between Tax and hiNOS mRNA expression. The transcriptional regulatory region of the hiNOS gene was activated by Tax in Jurkat, in which endogenous hiNOS is induced by Tax. Deletion analysis showed that the region of hiNOS encompassing nucleotides -159 to -111 contained the minimum Tax-responsive elements. Mutations in the NF-kappaB element at position -115 and -106 bp in the hiNOS promoter were still activated by Tax, and a Tax mutant defective for activation of the NF-kappaB pathway retained the ability to activate the hiNOS promoter. In addition, overexpression of the dominant-negative mutants of IkappaBalpha and I kappaBbeta failed to reduce Tax-induced activation of hiNOS gene. Furthermore, hiNOS mRNA was detected in leukemic cells from ATL patients. Our results show that the hiNOS promoter contains a minimum Tax-responsive element located between nucleotides -159 and -111, and imply that the expression of the hiNOS gene is involved in the pathogenesis of HTLV-I-associated diseases.
UI - 11023521
AU - El-Sabban ME; Nasr R; Dbaibo G; Hermine O; Abboushi N; Quignon F;
TI - Ameisen JC; Bex F; de The H; Bazarbachi A Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation.
SO - Blood 2000 Oct 15;96(8):2849-55
AD - Department of Human Morphology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I-induced transformation and apoptosis resistance by inducing I kappa B-alpha degradation, resulting in the activation of the NF-kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bax, or p53 expression. However, combined As and IFN induce the degradation of Tax, associated with an up-regulation of I kappa B-alpha resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kappa B complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I-induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kappa B pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-alpha in acute promyelocytic leukemia, provides strong rational for combined As-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)
UI - 11509123
AU - Beck JF; Brugger D; Brischwein K; Liu C; Bader P; Niethammer D; Gekeler
TI - V Anticancer drug-mediated induction of multidrug resistance-associated genes and protein kinase C isozymes in the T-lymphoblastoid cell line CCRF-CEM and in blasts from patients with acute lymphoblastic leukemias.
SO - Jpn J Cancer Res 2001 Aug;92(8):896-903
AD - Department of Pediatric Haematology/Oncology, University of Greifswald, Soldmannstr. 15, D-17487 Greifswald, Germany. firstname.lastname@example.org
The major determinants mediating drug resistance in acute lymphoblastic leukemias (ALL) unresponsive to chemotherapy, are still unclear. For example, it is still unknown whether selection or induction processes are responsible for drug resistance here or whether protein kinase C (PKC) isozymes contribute to the resistant phenotype. Therefore, inducibility of resistance factors or PKC isozymes genes was examined in CCRF-CEM cells treated with diverse anticancer drugs--adriamycin, camptothecin, etoposide or vincristine--at sublethal concentrations for 24 h. MDR1, MRP1, LRP and PKC isozyme alpha, beta(1), beta(2), epsilon, iota, eta, theta, zeta gene expression was determined by cDNA-PCR. We found significant dose-dependent, mostly combined, induction of the MDR1, MRP1 and LRP genes. Significantly enhanced gene expression of the majority of PKC isozyme genes was found after treatment with camptothecin. PKCzeta was upregulated throughout by each anticancer drug applied in this setting. A series of selected CCRF-CEM-derived multidrug resistance (MDR) sublines also showed enhanced expression of the PKC isozymes compared to the parental cell line. MDR1 and PKCeta gene expression levels were correlated highly significantly. Blasts from two patients with ALL during the first week of monotherapy with steroids revealed combined induction of the MDR1, multidrug resistance-associated protein 1 (MRP1), lung cancer resistance-related protein (LRP) and most PKC isozymes, predominantly PKCzeta. Another patient with T-ALL, who failed to respond to four months of intensive chemotherapy, showed an enhanced MRP1 gene expression combined with markedly overexpression of PKCeta and PKCtheta. Furthermore, the camptothecin and etoposide-mediated induction of resistance factors in the CCRF-CEM cell line could be suppressed by staurosporine, a rather unspecific inhibitor of protein kinases. However, selective inhibitors of PKC isozymes (bisindolylmaleimide GO 6850, indolocarbazole GO 6976) produced no significant effects here. Therefore, the PKC isozymes eta, theta and zeta are of interest as potential targets to overcome drug resistance in ALL.
UI - 11739184
AU - Mahieux R; Pise-Masison C; Gessain A; Brady JN; Olivier R; Perret E;
TI - Misteli T; Nicot C Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1- and type 2-infected cells by a caspase-3-dependent mechanism involving Bcl-2 cleavage.
SO - Blood 2001 Dec 15;98(13):3762-9
AD - Unite d'Epidemiologie et Physiopathologie des Virus Oncogenes, Institut Pasteur, Paris, France. email@example.com
Treatment of patients with adult T-cell leukemia-lymphoma (ATLL) using conventional chemotherapy has limited benefit because human T-cell leukemia virus type 1 (HTLV-1) cells are resistant to most apoptosis-inducing agents. The recent report that arsenic trioxide induces apoptosis in HTLV-1-transformed cells prompted investigation of the mechanism of action of this drug in HTLV-1 and HTLV-2 interleukin-2-independent T cells and in HTLV-1-immortalized cells or in ex vivo ATLL samples. Fluorescence-activated cell sorter analysis, fluorescence microscopy, and measures of mitochondrial membrane potential (Delta Psi m) demonstrated that arsenic trioxide alone was sufficient to induce programmed cell death in all HTLV-1 and -2 cells tested and in ATLL patient samples. I kappa B-alpha phosphorylation strongly decreased, and NF-kappa B translocation to the nucleus was abrogated. Expression of the antiapoptotic protein Bcl-X(L), whose promoter is NF-kappa B dependent, was down-regulated. The collapse of Delta Psi m and the release of cytochrome c to the cytosol resulted in the activation of caspase-3, as demonstrated by the cleavage of PARP. A specific caspase-3 inhibitor (Ac-DEVD-CHO) could reverse this phenotype. The antiapoptotic factor Bcl-2 was then cleaved, converting it to a Bax-like death effector. These results demonstrated that arsenic trioxide induces apoptosis in HTLV-1- and -2-infected cells through activation of the caspase pathway.
UI - 12123433
AU - Monge P; Wesseling C; Rodriguez AC; Cantor KP; Weiderpass E; Reutfors J;
TI - Ahlbom A; Partanen T Childhood leukaemia in Costa Rica, 1981-96.
SO - Paediatr Perinat Epidemiol 2002 Jul;16(3):210-8
AD - Central American Institute for Studies on Toxic Substances (IRET), Universidad Nacional, PO Box 86-3000, Heredia, Costa Rica. firstname.lastname@example.org
Childhood leukaemia incidence in Costa Rica during 1981-96, among the highest in the world, was analysed by histology, gender, birth year, time period of diagnosis, age at diagnosis and region. Numbers of cases were extracted from the database of the National Cancer Registry (RNT) of Costa Rica. Person-years at risk were calculated from census data and post-census population estimates. During the follow-up, 918 cases of leukaemia in children under 15 years (510 boys, 408 girls) were reported to the RNT (41% of all childhood malignancies), with an overall age-standardised incidence rate of 56 per million person-years. Acute lymphocytic leukaemia (ALL) represented 79% and acute non-lymphocytic leukaemia (ANLL) 16% of the cases, with rates of 43 and 9 per million person-years respectively. There were downward trends in incidence of total leukaemias, ALL and ANLL and 'not otherwise specified' (NOS) combined. Incidence of ALL was highest at 1-4 years of age in boys and girls, whereas ANLL peaked in girls during the first year of life. During 1991-96, the decrease in ALL was significant (P = 0.042). A multivariable Poisson regression model identified significant excesses of ALL for boys, for age groups 1-4 and 5-9 years and for three out of seven regions. Possible reasons for the high rates in Costa Rica are discussed.
UI - 11299818
AU - Yamada M; Asanuma K; Kobayashi D; Moriai R; Yajima T; Yagihashi A;
TI - Yamamori S; Watanabe N Quantitation of multiple myeloma oncogene 1/interferon-regulatory factor 4 gene expression in malignant B-cell proliferations and normal leukocytes.
SO - Anticancer Res 2001 Jan-Feb;21(1B):633-8
AD - Division of Laboratory Diagnosis, Sapporo Medical University, School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan.
BACKGROUND: We studied multiple myeloma oncogene 1/interferon-regulatory factor 4 (MUM1/IRF4) mRNA expression in various malignant human hematopoietic cell lines and normal leukocyte fractions. MATERIALS AND METHODS: A quantitative reverse transcription-polymerase chain reaction was used to assess expression and chromosomes were examined for anomalies by fluorescent in situ hybridization. RESULTS: Among 12 cell lines examined, mRNA transcripts were expressed only in B-lymphoblastic and myeloma cell lines. Myeloma cells and malignant cell lines derived from mature B cells expressed more transcript than cell lines derived from immature B cells. Transcript levels, however, showed no association with chromosomal translocations. Expression in B-cell fractions from healthy donors was much less than in the malignant cells. In addition, MUM1/IRF4 mRNA expressed in samples from patients with acute lymphoblastic leukemia derived from B cells but not T cells. CONCLUSION: Our results suggested that MUM1/IRF4 gene expression is related to stage of differentiation of malignant B cells and they indicated the possibility that the quantitative analysis of MUM1/IRF4 gene is a useful tool for detection of malignant B-cell proliferations in clinical laboratory tests.
UI - 1964581
AU - Bernard O; Guglielmi P; Jonveaux P; Cherif D; Gisselbrecht S; Mauchauffe
TI - M; Berger R; Larsen CJ; Mathieu-Mahul D Two distinct mechanisms for the SCL gene activation in the t(1;14) translocation of T-cell leukemias.
SO - Genes Chromosomes Cancer 1990 Jan;1(3):194-208
AD - U301 INSERM CNRS, Institute de Genetique Moleculaire, France.
Molecular study of a t(1;14)(p32;q11) translocation found in an acute T-cell leukemia (Kd cells) with a relatively mature phenotype is reported. Complex DNA rearrangements were characterized in the TCR alpha/delta locus. Besides a productive V alpha/J alpha assembly found on the normal allele, two deletions within the J alpha cluster were identified in the translocated allele. The translocation breakpoints involved the TCR delta gene on chromosome 14 and the SCL locus on chromosome band Ip32 that was recently shown to be activated by the t(1;14) translocation of the DU 528 leukemic cell line. Significantly, both Kd and DU 528 translocation breakpoints were located at the boundaries of D delta or J delta segments and were clustered in a 10 kb genomic fragment of the SCL gene. The presence of recombination signal motifs (heptamer-12/23 bp spacer-nonamer) on both normal chromosome partners, and N nucleotide addition on both derivative chromosomes involved the recombinase system in the translocation event. The SCL locus was highly expressed as a 5 kb transcript in Kd cells and, as already reported, as a 2 kb transcript in DU 528 cells. Importantly, a 5 kb SCL transcript was also detected in immature nonlymphoid hematopoietic cells but not in normal mature T cells, suggesting that it might correspond to the normal SCL transcript. Taken together, our data support the notion that the involvement of the SCL gene in the leukemogenic process may occur through overexpression of an apparently normal transcript (Kd cells) or expression of a truncated RNA (DU 528 cells).
UI - 1311214
AU - Aplan PD; Lombardi DP; Reaman GH; Sather HN; Hammond GD; Kirsch IR
TI - Involvement of the putative hematopoietic transcription factor SCL in T-cell acute lymphoblastic leukemia.
SO - Blood 1992 Mar 1;79(5):1327-33
AD - National Cancer Institute/Navy Medical Oncology Branch, National Naval Medical Center, Bethesda, MD 20889.
The SCL gene, initially discovered at the site of a translocation breakpoint associated with the development of a stem cell leukemia, encodes a protein that contains the highly conserved basic helix-loop-helix (bHLH) motif found in a large array of eukaryotic transcription factors. Recently, we have described a nonrandom, site-specific SCL rearrangement in several T-cell acute lymphoblastic leukemia (ALL) cell lines that juxtaposes SCL with a distinct transcribed locus, SIL. The SIL/SCL rearrangement was found in leukemic blasts from 11 of 70 (16%) newly diagnosed T-cell ALL patients, a prevalence substantially higher than that of the t(11;14) translocation, which has previously been reported as the most frequent nonrandom chromosomal abnormality in T-cell ALL. We did not detect the SIL/SCL rearrangement in the leukemic blasts from 30 patients with B-cell precursor ALL, indicating that the rearrangement was specific for T-cell ALL. Analysis of RNA from these patients indicated that an SIL/SCL fusion mRNA was formed, joining SIL and SCL in a head-to-tail fashion. The fusion occurs in the 5' untranslated region (UTR) of both genes, preserving the SCL coding region. The net result of this rearrangement is that SCL mRNA expression becomes regulated by the SIL promoter, leading to inappropriate SCL expression. The resultant inappropriate expression of this putative transcription factor may then contribute to leukemic transformation in T-cell ALL.
UI - 1402666
AU - Bernard O; Azogui O; Lecointe N; Mugneret F; Berger R; Larsen CJ;
TI - Mathieu-Mahul D A third tal-1 promoter is specifically used in human T cell leukemias.
SO - J Exp Med 1992 Oct 1;176(4):919-25
AD - U. 301 Institut National de la Sante et de la Recherche Medicale (INSERM)-Institut de Genetique Moleculaire (IGM), France.
A common feature of T cell acute lymphoblastic leukemias (T-ALLs) is the presence of structural alteration of the 5' part of the tal-1 locus, localized on chromosomal band 1p32. These alterations consist of either a t(1;14)(p32;q11) chromosomal translocation (3% of T-ALLs) or tald submicroscopic deletion (12-25% additional T-ALLs). We have characterized a case of T-ALL with t(1;14)(p32;q11) in which, unlike the majority of t(1;14), the recombination with the T cell receptor delta elements affected the 3' side of the tal-1 locus. In this case, tal-1 transcription is initiated from a promoter located within the fourth exon similarly to the DU 528 cell line. In a T-ALL bearing a t(1;14) affecting the 5' part of tal-1, two types of tal-1 transcripts were observed, namely those probably initiated from the D delta region juxtaposed to tal-1 by the translocation, and those from the exon 4 promoter. It is interesting that this exon 4 promotion was also found in leukemic T cell lines and T-ALL samples without apparent tal-1 genomic alteration. In contrast, no transcript initiated from the exon 4 promoter was found in T-ALL with tald1 or tald2 deletion. In these cells, tal-1 is expressed via SIL-tal-1 fused transcripts. Finally, this exon 4 initiation was detected neither in normal bone marrow, nor in malignant cells from the erythroid/megakaryocytic lineages. Taken as a whole, these data suggest that the exon 4 promoter is specifically active in T cell lineage.
UI - 1402676
AU - Aplan PD; Raimondi SC; Kirsch IR
TI - Disruption of the SCL gene by a t(1;3) translocation in a patient with T cell acute lymphoblastic leukemia.
SO - J Exp Med 1992 Nov 1;176(5):1303-10
AD - Navy Medical Branch, National Cancer Institute, Bethesda, Maryland 20889.
SCL gene disruptions are the most common chromosomal abnormality associated with the development of T cell acute lymphoblastic leukemia (ALL). Such disruptions can be the result of t(1;14) and t(1;7) translocations, as well as a cytogenetically undetectable interstitial deletion of chromosome 1. We present here a case of T cell ALL with a t(1;3)(p34;p21) translocation that also disrupts the SCL locus and leads to dysregulated SCL gene expression. This translocation, similar to previously reported SCL gene disruptions, appears to have been mediated, at least in part, by the V(D)J recombinase complex, since cryptic heptamer recognition sequences, as well as nontemplated N region nucleotide addition, are present at the breakpoints. The t(1;3) also disrupts a region on chromosome 3 characterized by alternating purine and pyrimidine residues, which can form a Z-DNA structure, reported to be prone to recombination events. A previously undescribed, evolutionarily conserved transcript unit is detected within 8 kb of the breakpoint on chromosome 3. This report extends the spectrum of recognized SCL translocations associated with T cell ALL, and underscores the contention that dysregulated SCL expression may be a causal event in T cell ALL.
UI - 7678994
AU - Mouthon MA; Bernard O; Mitjavila MT; Romeo PH; Vainchenker W;
TI - Mathieu-Mahul D Expression of tal-1 and GATA-binding proteins during human hematopoiesis.
SO - Blood 1993 Feb 1;81(3):647-55
AD - INSERM 91, Hopital Henri Mondor, Creteil, France.
Tal-1 rearrangements are associated with nearly 30% of human T acute lymphoblastic leukemia. Tal-1 gene encodes a putative transcription factor with a basic helix-loop-helix domain and is known to be predominantly expressed in hematopoietic cells. We investigated the pattern of tal-1 expression in purified human hematopoietic cells by in situ hybridization and reverse transcriptase polymerase chain reaction analysis. Both methods demonstrated that the tal-1 gene is expressed in megakaryocytes and erythroblasts as well as in basophilic granulocytes. In addition, our results indicate that the tal-1 1A promoter, which contains two consensus GATA-binding sites, is active mainly in these lineages. Because the GATA-1 gene is known to transactivate several genes specific for the erythroid, megakaryocytic, and mastocytic/basophilic lineages, we studied GATA-1 expression in these purified hematopoietic cells. We found that GATA-1 and tal-1 genes are coexpressed in these three lineages. Remarkably, the expression of both genes is downmodulated during erythroid and megakaryocytic terminal maturation. In immature hematopoietic cells, tal-1 and GATA-1 genes are coexpressed in committed progenitors cells (CD34+/CD38(2+)), whereas they are not detectable in the most primitive cells (CD34(2+)/CD38-). In contrast, GATA-2 is strongly expressed in both most primitive and committed progenitors cells, whereas GATA-3 is mostly detected in most primitive ones. Altogether our results strongly suggest that GATA-1 modulates the transcription of tal-1 during the differentiation of the erythroid, megakaryocytic, and basosophilic lineages.
UI - 8435335
AU - Borkhardt A; Repp R; Harbott J; Kreuder J; Lampert F
TI - Quantification of leukaemic cells based on heteroduplex formation of tal-1 gene sequences after PCR coamplification.
SO - Br J Haematol 1993 Jan;83(1):39-44
AD - Children's Hospital, University of Giessen, Germany.
Based on the high sensitivity of the polymerase chain reaction (PCR) several assays have already been described which can be applied to monitor minimal residual disease in patients with leukaemia. However, most of these approaches are only qualitative or semiquantitative at best. Moreover, the semiquantitative assays require rather large-scale procedures such as oligonucleotide hybridization or sampling of aliquots during the exponential phase of PCR amplification, which is time consuming and may be error prone. Using the deletion in the tal-1 gene as a clonal marker of malignant cells, which can be found in about 10-25% of T-cell acute lymphoblastic leukaemia, we have developed a rapid and simple PCR assay for the quantification of residual leukaemic cells. The assay is based on heteroduplex formation between standard and template DNA sequences after coamplification of both DNA sequences in the same PCR reaction. The sensitivity of this PCR approach allows the detection of neoplastic cells at frequency of at least 10(-4). Application of such an assay needs not to be restricted to patients harbouring a tal-1 gene deletion. It may easily be adapted to other clonal DNA markers of blast cells and therefore facilitate monitoring of minimal residual disease in many different kinds of leukaemia.
UI - 8459224
AU - Breit TM; Mol EJ; Wolvers-Tettero IL; Ludwig WD; van Wering ER; van
TI - Dongen JJ Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes.
SO - J Exp Med 1993 Apr 1;177(4):965-77
AD - Department of Immunology, University Hospital Dijkzigt/Erasmus University, Rotterdam, The Netherlands.
Site-specific deletions in the tal-1 gene are reported to occur in 12-26% of T cell acute lymphoblastic leukemias (T-ALL). So far two main types of tal-1 deletions have been described. Upon analysis of 134 T-ALL we have found two new types of tal-1 deletions. These four types of deletions juxtapose the 5' part of the tal-1 gene to the sil gene promoter, thereby deleting all coding sil exons but leaving the coding tal-1 exons undamaged. The recombination signal sequences (RSS) and fusion regions of the tal-1 deletion breakpoints strongly resemble the RSS and junctional regions of immunoglobulin/T cell receptor (TCR) gene rearrangements, which implies that they are probably caused by the same V(D)J recombinase complex. Analysis of the 134 T-ALL suggested that the occurrence of tal-1 deletions is associated with the CD3 phenotype, because no tal-1 deletions were found in 25 TCR-gamma/delta + T-ALL, whereas 8 of the 69 CD3- T-ALL and 11 of the 40 TCR-alpha/beta + T-ALL contained such a deletion. Careful examination of all TCR genes revealed that tal-1 deletions exclusively occurred in CD3- or CD3+ T-ALL of the alpha/beta lineage with a frequency of 18% in T-ALL with one deleted TCR-delta allele, and a frequency of 34% in T-ALL with TCR-delta gene deletions on both alleles. Therefore, we conclude that alpha/beta lineage commitment of the T-ALL and especially the extent of TCR-delta gene deletions determines the chance of a tal-1 deletion. This suggests that tal-1 deletions are mediated via the same deletion mechanism as TCR-delta gene deletions.
UI - 8471769
AU - Bash RO; Crist WM; Shuster JJ; Link MP; Amylon M; Pullen J; Carroll AJ;
TI - Buchanan GR; Smith RG; Baer R Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study.
SO - Blood 1993 Apr 15;81(8):2110-7
AD - Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9048.
Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.
UI - 8350619
AU - Janssen JW; Ludwig WD; Sterry W; Bartram CR
TI - SIL-TAL1 deletion in T-cell acute lymphoblastic leukemia.
SO - Leukemia 1993 Aug;7(8):1204-10
AD - Department of Pediatrics II, University of Ulm, Germany.
The TAL1 gene on chromosome 1 encodes a hematopoietic transcription factor. Disruption of TAL1 via chromosomal translocation or a site-specific deletion has been reported in up to 30% of T-cell acute lymphoblastic leukemias (T-ALL). Here we used a polymerase chain reaction (PCR) assay to identify the 90 kb SIL-TAL1 deletion in a group of 19 cutaneous T-cell lymphomas and a series of 142 T-ALL patients (76 children, 66 adults). While none of the T-cell lymphoma exhibited a SIL-TAL1 recombination, seven T-ALL cases showed a type d1 and two patients a type d2 deletion. Of pediatric T-ALL, 9% (7/76) and of adult patients only 3% (2/66) were characterized by this genomic lesion. The deletion correlated with commitment to the T-cell receptor (TCR) alpha beta lineage, but lacked association with a distinct maturation stage. Sequence analysis of SIL-TAL1 breakpoints revealed marked heterogeneity at the junctional region among the nine patients due to random deletion and insertion of N-region nucleotides or templated P-nucleotide addition mediated via illegitimate V(D)J recombinase action. Clonospecific oligomer probes in conjunction with PCR allowed the detection of minimal residual disease in one out of four patients monitored during complete hematologic remission.
UI - 8255100
AU - Breit TM; Beishuizen A; Ludwig WD; Mol EJ; Adriaansen HJ; van Wering ER;
TI - van Dongen JJ tal-1 deletions in T-cell acute lymphoblastic leukemia as PCR target for detection of minimal residual disease.
SO - Leukemia 1993 Dec;7(12):2004-11
AD - Department of Immunology, Erasmus University/University Hospital Dijkzigt, Rotterdam, The Netherlands.
Polymerase chain reaction (PCR) techniques based on amplification and identification of leukemia-specific DNA sequences provide a sensitive diagnostic method for detection of minimal residual disease (MRD) with a detection limit of 10(-5) to 10(-6) (1-10 malignant cells in 10(6) normal cells). To date, the main leukemia-specific DNA sequences used as PCR targets in detection of MRD are breakpoint fusion regions of chromosome translocations and junctional regions of rearranged immunoglobulin (Ig) or T-cell receptor (TcR) genes. The recently identified tal-1 deletions involving the sil and tal-1 genes, provide a potential MRD-PCR target. tal-1 deletions are site-specific because they are mediated via recombination signal sequences homologous to Ig/TcR genes. In line with this homology, tal-1 deletions also show random insertion and deletion of nucleotides at their breakpoints, resulting in highly variable breakpoint fusion regions. The fusion region diversity can be applied to design patient-specific oligonucleotide probes. Our Southern blot analyses of a large series of 313 acute leukemias with a specific tal-1 deletion probe (SILDB) demonstrated that tal-1 deletions exclusively occur in T-cell acute lymphoblastic leukemia (T-ALL) and not in precursor B-ALL or acute non-lymphocytic leukemias. In addition, we did not detect tal-1 deletions in normal blood cells and normal thymocytes by PCR analysis. The diversity observed in tal-1 deletion fusion regions with an average insertion and deletion of approximately 7 and approximately 6 nucleotides, respectively, allowed us to design fusion-region-specific probes. The specificity of the fusion-region probes was proven and the detection limit of the MRD-PCR technique was tested in a series of dilution experiments. The observed detection limit of 10(-5) indicates that tal-1 deletions in T-ALL represent ideal leukemia-specific PCR targets for detection of MRD.
UI - 8079047
AU - Breit TM; Wolvers-Tettero IL; van Dongen JJ
TI - Phenotypic and genotypic characteristics of human early T-cell differentiation: the T-cell acute lymphoblastic leukaemia model.
SO - Res Immunol 1994 Feb;145(2):139-43; discussion 155-8
AD - Department of Immunology, University Hospital Dijkzigt/Erasmus University, Rotterdam, The Netherlands.
UI - 8167548
AU - Goldfarb AN; Greenberg JM
TI - T-cell acute lymphoblastic leukemia and the associated basic helix-loop-helix gene SCL/tal.
SO - Leuk Lymphoma 1994 Jan;12(3-4):157-66
AD - Case Western Reserve University, Institute of Pathology, Cleveland, Ohio 44106-4943.
T-cell acute lymphoblastic leukemia (T-ALL) is a relatively uncommon disease, constituting only approximately 15% of newly diagnosed acute lymphoblastic leukemias (ALL) in the United States, or roughly 300 cases per year. Outside of the United States, in countries such as Egypt and India, T-ALL may represent as much as 50% of all ALL's but still remains an overall rare disease. The clinical importance of T-ALL lies in its poor responsiveness to therapy that has proved highly effective with standard B-cell precursor ALL (BCP-ALL). The scientific importance of human T-ALL has resided in its role as a cancer prototype, permitting the identification of novel genes centrally involved in both neoplastic change and normal cellular differentiation. One of these genes, SCL/tal, has received significant attention due to its intimate involvement in T-ALL, as well as in normal hematopoiesis. Although a tremendous amount has been recently discovered about SCL/tal, its exact roles in leukemogenesis and normal hematopoiesis remain obscure.
UI - 8182934
AU - Neale GA; Pui CH; Mahmoud HH; Mirro J Jr; Crist WM; Rivera GK; Goorha RM
TI - Molecular evidence for minimal residual bone marrow disease in children with 'isolated' extra-medullary relapse of T-cell acute lymphoblastic leukemia.
SO - Leukemia 1994 May;8(5):768-75
AD - Dept of Virology and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Central nervous system (CNS) relapse confers a poor prognosis in children with acute lymphoblastic leukemia (ALL). It is uncertain whether morphologically undetectable leukemia is present in the bone marrow at the time of CNS relapse, or whether the CNS acts as a 'sanctuary' site to allow reseeding of the marrow at a later time. We examined DNA from bone marrow samples from six patients with T-cell ALL with isolated CNS relapse using sensitive polymerase chain reaction (PCR) assays to detect minimal residual disease. One of these PCR assays was based on amplification of leukemia-specific TCR-delta gene rearrangements, while the other assay relied upon detection of the c-tal deletion. In four patients, where bone marrow samples were taken at the time of CNS relapse, residual disease was detectable in every sample at a level below morphological detection. In addition, three patients had residual disease detected in their subsequent bone marrow when CNS disease was not evident. Our findings, although preliminary, suggest that relapse of leukemia in the CNS reflects resurgence of the disease in the bone marrow that is first detected clinically in the CNS. The concomitant molecular detection of bone marrow leukemia at time of 'isolated' CNS relapse in children with T-cell ALL explains subsequent bone marrow relapse in some of these children, and argues for intensive systemic therapy of these patients.
UI - 7773964
AU - Huang W; Kuang SQ; Huang QH; Dong S; Zhang T; Gu LJ; Ching LM; Chen SJ;
TI - Chang LC; Chen Z RT/PCR detection of SIL-TAL-1 fusion mRNA in Chinese T-cell acute lymphoblastic leukemia (T-ALL).
SO - Cancer Genet Cytogenet 1995 May;81(1):76-82
AD - Shanghai Institute of Hematology, Rui-Jin Hospital, Samuel Waxman Cancer Research Foundation, China.
The TAL-1 gene is located on chromosome 1p32. In about 20% of T-cell acute lymphoblastic leukemias (T-ALL), this gene is disrupted in its 5' portion by a site-specific 100-kg deletion and is fused with the 5' part of the SIL gene, to form SIL-TAL-1 chimeric gene. In this study, we established a "nested" retrotranscriptase/polymerase chain react