Asunto(s)

Cromosomas Humanos Par 1 , Cromosomas Humanos Par 7 , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/inducido químicamente , Adulto , Anciano , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/genética , Translocación Genética

RESUMEN

Frameshift mutations of the nucleophosmin gene (NPM1) were recently reported as a frequently occurring abnormality in patients with de novo acute myeloid leukemia (AML). To evaluate the frequency of NPM1 mutations in patients with therapy-related myelodysplasia (t-MDS) and therapy-related AML (t-AML), and their possible association to type of previous therapy and to other gene mutations, 140 patients with t-MDS or t-AML were analyzed for mutations of NPM1. NPM1 mutations were observed in 7 of 51 patients presenting as overt t-AML, as compared to only 3 of 89 patients presenting as t-MDS (P=0.037). The mutations were not related to any specific type of previous therapy, but they were significantly associated with a normal karyotype and mutations of FLT3 (P=0.0002 for both comparisons). Only 1 of 10 patients with NPM1 mutations presented chromosome aberrations characteristic of therapy-related disease, and 7q-/-7, the most frequent abnormalities of t-MDS/t-AML, were not observed (P=0.002). This raises the question whether some of the cases presenting NPM1 mutations were in fact cases of de novo leukemia. The close association to class I mutations and the inverse association to class II mutations suggest mutations of NPM1 as representing a class II mutation-like abnormality in AML.

Asunto(s)

Leucemia Mieloide Aguda/genética , Mutación , Neoplasias Primarias Secundarias/genética , Proteínas Nucleares/genética , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Errores Diagnósticos , Femenino , Frecuencia de los Genes , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Proteínas Mutantes , Neoplasias Primarias Secundarias/diagnóstico , Nucleofosmina , Tirosina Quinasa 3 Similar a fms/genética

RESUMEN

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytogenetic characteristics, therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are often considered as separate entities and are not subdivided. Alternative genetic pathways were previously proposed in t-MDS and t-AML based on cytogenetic characteristics. An increasing number of gene mutations are now observed to cluster differently in these pathways with an identical pattern in de novo and in t-MDS and t-AML. An association is observed between activating mutations of genes in the tyrosine kinase RAS-BRAF signal-transduction pathway (Class I mutations) and inactivating mutations of genes encoding hematopoietic transcription factors (Class II mutations). Point mutations of AML1 and RAS seem to cooperate and predispose to progression from t-MDS to t-AML. Recently, critical genetic effects underlying 5q-/-5 and 7q-/-7 have been proposed. Their association and cooperation with point mutations of p53 and AML1, respectively, extend the scenario of cooperating genetic abnormalities in MDS and AML. As de novo and t-MDS and t-AML are biologically identical diseases, they ought to be subclassified and treated similarly.

Asunto(s)

Leucemia Mieloide Aguda/genética , Mutación/genética , Síndromes Mielodisplásicos/genética , Neoplasias Primarias Secundarias/genética , Humanos , Transducción de Señal/genética , Factores de Transcripción/genética

RESUMEN

Alternative genetic pathways were previously outlined in the pathogenesis of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) based on cytogenetic characteristics. Some of the chromosome aberrations, the recurrent balanced translocations or inversions, directly result in chimeric rearrangement of genes for hematopoietic transcription factors (class II mutations) which disturb cellular differentiation. Other genetic abnormalities in t-MDS and t-AML comprise activating point mutations or internal tandem duplications of genes involved in signal transduction as tyrosine kinase receptors or genes more downstream in the RAS-BRAF pathway (class I mutations). The alternative genetic pathways of t-MDS and t-AML can now be further characterized by a different clustering of six individual class I mutations and mutations of AML1 and p53 in the various pathways. In addition, there is a significant association between class I and class II mutations possibly indicating cooperation in leukemogenesis, and between mutations of AML1 and RAS related to subsequent progression from t-MDS to t-AML. Therapy-related and de novo myelodysplasia and acute myeloid leukemia seem to share genetic pathways, and surprisingly gene mutations were in general not more frequent in patients with t-MDS or t-AML as compared to similar cases of de novo MDS and AML studied previously.

Asunto(s)

Antineoplásicos Alquilantes/efectos adversos , Leucemia Mieloide/inducido químicamente , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Aberraciones Cromosómicas , Humanos , Mutación

Asunto(s)

Leucemia Mieloide/genética , Mutación , Síndromes Mielodisplásicos/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Enfermedad Aguda , Humanos , Janus Quinasa 2 , Cariotipificación , Leucemia Mieloide/enzimología , Síndromes Mielodisplásicos/enzimología

RESUMEN

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with -7/7q- (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted 'class-I' mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted 'class-II' mutations) (P=0.046) suggesting their cooperation in leukemogenesis.

Asunto(s)

Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Neoplasias Primarias Secundarias/genética , Mutación Puntual , Proteínas Tirosina Quinasas Receptoras/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Proteína alfa Potenciadora de Unión a CCAAT/genética , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Leucemia Mieloide/etiología , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas B-raf/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Transducción de Señal , Tirosina Quinasa 3 Similar a fms , Proteínas ras/genética

RESUMEN

Amplification or duplication of the AML1 gene at chromosome band 21q22 was detected by FISH using a locus-specific probe in three out of 171 unselected patients with therapy-related myelodysplasia (t-MDS) or t-AML (1.7%). In two patients AML1 signals were located tandemly on derivative chromosomes, in one patient on a dic(9;21) and in the the other patient on a derivative chromosome 18 made up of interchanging layers of material from chromosomes 9, 14, 18, and 21. In the third patient three single supernumerary copies of AML1 were located on derivatives of chromosomes 19 and 21. All three patients were older, had previously received therapy with alkylating agents without topoisomerase II inhibitors, had complex karyotypes including abnormalities of chromosomes 5 or 7, and presented acquired point mutations of the TP53 gene. No point mutations of the AML1 gene were observed. The results support a pivotal role of impaired TP53 function in the development of gene amplification or duplication in t-MDS and t-AML.

Asunto(s)

Cromosomas Humanos Par 21/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes/genética , Duplicación de Gen , Genes p53 , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Mapeo Cromosómico , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Exones , Humanos , Leucemia Mieloide Aguda/mortalidad , Mutación , Síndromes Mielodisplásicos/mortalidad , Análisis de Supervivencia

RESUMEN

The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.

Asunto(s)

Proteínas de Ciclo Celular/genética , Cromosomas Humanos Par 7/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Eliminación de Gen , Enfermedad de Hodgkin/terapia , Leucemia Mieloide/genética , Proteínas Supresoras de Tumor , Enfermedad Aguda , Aberraciones Cromosómicas , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , ADN de Neoplasias/genética , Inhibidores Enzimáticos , Femenino , Silenciador del Gen , Genes Supresores de Tumor , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Recurrencia Local de Neoplasia/genética , Neoplasias Primarias Secundarias/genética , Reacción en Cadena de la Polimerasa , Pronóstico , Regiones Promotoras Genéticas/genética , Inducción de Remisión , Proteína p14ARF Supresora de Tumor/genética

RESUMEN

New insights into causative factors for the development of myelodysplasia (MDS) and acute myeloid leukemia (AML), with associations to specific cytogenetic and genetic abnormalities have been obtained primarily from studies of patients with the therapy-related subsets of the two diseases. Current knowledge now makes it possible to distinguish between at least seven major genetic subgroups of MDS and AML, and has directed research towards more specific causative factors also for de novo MDS and AML.

Asunto(s)

Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Aberraciones Cromosómicas , Humanos , Leucemia Mieloide/diagnóstico , Síndromes Mielodisplásicos/diagnóstico

Asunto(s)

Antineoplásicos/uso terapéutico , Cromosomas Humanos Par 8 , Hematopoyesis , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Trisomía , Adulto , Anciano , Benzamidas , Hematopoyesis/genética , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/fisiopatología , Persona de Mediana Edad , Cromosoma Filadelfia

RESUMEN

Eighty-two unselected cases of therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) were investigated for internal tandem duplications of the FLT3 gene (FLT3/ITD), for internal tandem duplications of the MLL gene (MLL/ITD) and for mutations of the WT1 gene. FLT3/ITD were observed in three patients, another two patients presented MLL/ITD whereas mutations of the WT1 gene were not observed. All FLT3/ITD included the tyrosine-rich stretch between codons 589 and 599, and both MLL/ITD presented break points within Alu-repeats, as previously observed in de novo AML. The ITD were not related to any specific type of previous therapy, but three out of the five cases were observed among only six patients with overt t-AML and a normal karyotype (P = 0.0043). Interestingly, one of the patients with FLT3/ITD presented overt t-AML of subtype M1 with a normal karyotype after treatment with an alkylating agent. Complete remission was observed following treatment with daunorubicin and cytosine arabinoside, but after 37 months the patient relapsed with t-AML of subtype M3 with a t(15;17) and the same FLT3/ITD was still present. Thus FLT3/ITD may in this case represent a primary event in leukemogenesis, whereas the t(15;17) may represent a secondary event most likely induced by subsequent therapy. In conclusion, FLT3/ITD and MLL/ITD are mainly observed in uncharacteristic cases of t-AML with a normal karyotype and unrelated to previous therapy for which reason they could represent sporadic cases of de novoAML.

Asunto(s)

Proteínas de Unión al ADN/genética , Duplicación de Gen/efectos de los fármacos , Leucemia Mieloide/genética , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes , Proteínas Tirosina Quinasas Receptoras/genética , Factores de Transcripción , Enfermedad Aguda , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Secuencia de Bases , Terapia Combinada/efectos adversos , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Cariotipificación , Leucemia Mieloide/etiología , Masculino , Persona de Mediana Edad , Mutación , Proteína de la Leucemia Mieloide-Linfoide , Neoplasias Primarias Secundarias/etiología , Secuencias Repetidas en Tándem/genética , Translocación Genética , Proteínas WT1/genética , Tirosina Quinasa 3 Similar a fms

RESUMEN

A highly increased risk of myelodysplasia (MDS) and acute myeloid leukaemia (AML) is well established in patients previously treated for other malignancies with alkylating agents or topoisomerase II inhibitors. More recently, single cases of acute lymphoblastic leukaemia (ALL), often presenting balanced translocations involving chromosome band 11q23, have been observed. We present two such cases with t(4;11)(q21;q23), one of whom had previously received only single-agent chemotherapy with 4-epi-doxorubicin. A review of the literature since 1992 including these two patients reveals a total of 23 cases of ALL or lymphoblastic lymphoma after chemotherapy presenting balanced translocations to 11q23. All 23 patients had previously received at least one topoisomerase II inhibitor, and in two patients 4-epi-doxorubicin had been administered as single-agent chemotherapy for breast cancer. The latency period to development of t-ALL was 24 months or less in 20 out of 22 cases. The MLL gene was found to be rearranged in 14 out of 14 cases, and in three out of six cases the breakpoint was at the telomeric part of the gene, as observed in most cases of AML following therapy with topoisomerase II inhibitors. These results indicate that patients with ALL and balanced translocations to chromosome band 11q23 following chemotherapy with topoisomerase II inhibitors in the future should be included with cases of MDS or AML in calculations of risk of leukaemia.

Asunto(s)

Antineoplásicos/efectos adversos , Doxorrubicina/análogos & derivados , Doxorrubicina/efectos adversos , Leucemia Prolinfocítica/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inducido químicamente , Proto-Oncogenes , Inhibidores de Topoisomerasa II , Factores de Transcripción , Adulto , Neoplasias Óseas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 4 , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Proteína de la Leucemia Mieloide-Linfoide , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Seminoma/complicaciones , Seminoma/tratamiento farmacológico , Neoplasias Testiculares/complicaciones , Neoplasias Testiculares/tratamiento farmacológico , Translocación Genética

RESUMEN

Gene amplification is a rare phenomenon in acute leukemia, but recently amplification of specific chromosome bands containing genes rearranged in leukemia-specific balanced chromosome translocations has been reported in a few cases. We detected duplication or amplification of chromosome band 11q23 with 3-7 copies of the MLL gene by fluorescence in situ hybridization in 12 out of 70 unselected patients with therapy-related myelodysplasia or acute myeloid leukemia (17%). In all but one case, the supernumerary copies of MLL were located to previously unidentified marker chromosomes or unbalanced translocations. In 4 of the 12 patients, 2-6 copies were located together on the same chromosome arm representing amplification, 7 patients had single, extra duplicated copies of MLL, whereas both amplification and duplication were observed in the same cell in 1 patient. Comparative genomic hybridization demonstrated gain of varying, often large parts of 11q in five patients. The MLL gene was shown to be unrearranged in all 12 patients. Seven out of eight patients with duplication or amplification of MLL had mutations of TP53. Patients with supernumerary copies of MLL were in general older (P = 0.007) and had a shorter survival (P < 0.001) compared to other patients. Duplication or amplification of MLL was significantly associated with a complex karyotype (P = 0.002), with deletion or loss of 5q (P = 0.001), and with prior therapy with alkylating agents. These results support the existence of a specific genetic pathway in t-MDS and t-AML with many previously unidentified chromosome aberrations demonstrated to represent extra copies of parts of 11q, including the unrearranged MLL gene.

Asunto(s)

Alquilantes/efectos adversos , Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 11/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes/genética , Duplicación de Gen , Genes p53/genética , Leucemia Mieloide/genética , Mutación/genética , Síndromes Mielodisplásicos/genética , Proto-Oncogenes , Factores de Transcripción , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Alquilantes/uso terapéutico , Aberraciones Cromosómicas/inducido químicamente , Bandeo Cromosómico , Trastornos de los Cromosomas , Análisis Citogenético/métodos , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteína de la Leucemia Mieloide-Linfoide , Hibridación de Ácido Nucleico/métodos , Recurrencia

RESUMEN

PURPOSE: To study mutations and loss of heterozygosity (LOH) of p53 in therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML). PATIENTS AND METHODS: Fifty-two unselected patients with t-MDS and 25 patients with t-AML were studied by polymerase chain reaction (PCR)-single-strand conformational polymorphism (SSCP) at the DNA level and by reverse transcriptase (RT)-PCR-SSCP at the mRNA level, and cases with aberrant SSCP patterns were sequenced. RESULTS: Somatically acquired mutations of p53 were observed in 21 of 77 cases of t-MDS or t-AML, and 19 of these 21 patients had received alkylating agents. Single-base substitutions at A:T pairs were more common in t-MDS and t-AML, whereas single-base substitutions at G:C pairs are most common in MDS and AML de novo and in solid tumors. Six patients demonstrated a cytogenetic loss of 17p13, and these six and an additional nine patients with p53 mutations demonstrated LOH of p53 at the DNA or mRNA level. This suggests a cytogenetic loss of the normal p53 allele in these nine cases combined with duplication of the homologous chromosome 17 carrying the mutated p53 allele. Mutations of p53 were significantly associated with deletion or loss of 5q (P <.0001) and a complex karyotype (P =.0001), but surprisingly were not associated with deletion or loss of 7q (P =.73), and were infrequent in patients with balanced chromosome translocations (P =.03). Mutations of p53 were more common in older patients (P =.036) and were associated with an extremely poor prognosis (P =.014), apparently restricted to the 15 cases with LOH of p53 ( P =.046). CONCLUSION: Mutations with loss of function of p53 are significantly associated with deletion or loss of 5q in t-MDS and t-AML after previous treatment with alkylating agents and are associated with genetic instability.

Asunto(s)

Antineoplásicos Alquilantes/efectos adversos , Genes p53/genética , Leucemia Mieloide/inducido químicamente , Leucemia Mieloide/genética , Pérdida de Heterocigocidad , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/genética , Neoplasias Primarias Secundarias/genética , Adulto , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Niño , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 5/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Pronóstico

Asunto(s)

Aberraciones Cromosómicas , Análisis Citogenético , Neoplasias/genética , Hibridación de Ácido Nucleico/métodos , ADN de Neoplasias/metabolismo , Humanos , Hibridación Fluorescente in Situ

RESUMEN

Therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) after high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT) for malignant diseases have become an important problem. The actuarial risk has varied, but has often been high if compared to the risk after conventional therapy. Prior chemotherapy with large cumulative doses of alkylating agents is the most important risk factor. In addition, patient age and previous radiotherapy, particularly the use of total body irradiation (TBI) in the preparative regimen for ASCT, have been identified as risk factors. In 3 studies, patients transplanted with CD34(+ )cells from peripheral blood after chemotherapy priming showed a higher risk of t-MDS or t-AML than patients transplanted with cells isolated from the bone marrow without priming. To what extent this higher risk relates to the prior therapy with a different contamination with preleukemic, hematopoietic precursors of the CD34(+) cells obtained by the 2 methods, or is a direct result of chemotherapy priming, or of an increasing awareness of these complications, remains to be determined. The latent period from ASCT to t-MDS and t-AML has often been short, 12 months or less in 27% of the patients. Bone marrow pathology of early cases of t-MDS after ASCT has often been neither diagnostic nor prognostic, but most patients presented chromosome aberrations, primarily deletions or loss of the long arms of chromosomes 5 and 7. The prognosis was in general poor, although 17% with indolent t-MDS survived more than 18 months from diagnosis, and most of these presented a normal karyotype or a single chromosome aberration.

Asunto(s)

Antineoplásicos/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide/etiología , Síndromes Mielodisplásicos/etiología , Neoplasias Primarias Secundarias/etiología , Neoplasias/terapia , Enfermedad Aguda , Aberraciones Cromosómicas , Humanos , Leucemia Mieloide/inducido químicamente , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/genética , Neoplasias/tratamiento farmacológico , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/genética , Factores de Riesgo , Trasplante Autólogo , Irradiación Corporal Total/efectos adversos

RESUMEN

Dicentric chromosomes are observed in many malignant diseases including myelodysplasia (MDS) and acute myeloid leukemia (AML) and have often been observed in a subset of these diseases, namely therapy-related MDS (t-MDS) and AML (t-AML). Using fluorescence in situ hybridization (FISH) with centromere-specific probes, we investigated the frequency and type of dicentric chromosomes in 180 consecutive patients with t-MDS and t-AML and in 231 consecutive patients with de novo MDS and AML, whose karyotypes had been studied previously by conventional G-banding. Twenty-seven out of 180 patients with t-MDS or t-AML presented dicentric chromosomes compared to only seven out of 231 patients with de novo disease (P = 0.00003). A dic(1q;7p) was observed in 10 cases, a dic(5p;17q) was observed in six cases, whereas various isodicentric chromosomes were observed in six cases. Excluding these six cases with isodicentrics, all 25 patients with dicentric chromosomes had involvement of at least one of the chromosome arms 1q, 5p, or 7p resulting in monosomy for 5q or 7q, and/or trisomy for 1q. Patients with dicentric chromosomes presented significantly more often as t-MDS compared to patients without dicentrics (P = 0.046), and the presence of a dicentric chromosome was significantly related to previous therapy with alkylating agents (P = 0.026). Thus, only one out of 27 patients with a dicentric chromosome had not previously received an alkylating agent. A specific susceptibility to breakage at the centromere after exposure to alkylating agents is suggested and may explain the frequent loss of whole chromosomes, in particular chromosomes 5 and 7 in t-MDS and t-AML, if the breaks are not followed by rejoining. Leukemia (2000) 14, 105-111.

Asunto(s)

Antineoplásicos Alquilantes/efectos adversos , Centrómero , Aberraciones Cromosómicas , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide/inducido químicamente , Síndromes Mielodisplásicos/inducido químicamente

RESUMEN

Increased risk of acute myeloid leukaemia has been reported in aircrew, possibly in association with cosmic radiation. We studied the cytogenetics of seven aircrew members who had acute myeloid leukaemia or myelodysplasia and found deletion or loss of chromosome 7 in four. The same abnormality was found in eight of 19 patients with leukaemia after radiotherapy alone. By comparison, only 81 of 761 unselected cases of myelodysplasia or acute myeloid leukaemia had the same cytogenetic abnormalities. Our results support the concept that deletions or loss of the long arm of chromosome 7 in myelodysplasia and acute myeloid leukaemia could indicate previous exposure to ionising radiation.

Asunto(s)

Cromosomas Humanos Par 7 , Eliminación de Gen , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/genética , Traumatismos por Radiación/complicaciones , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

During the period from 1995 to 1997, we studied 19 new cases of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), extending our series to 180 consecutive cases: 123 patients with t-MDS and 57 patients with t-AML. Cytogenetically unrelated clones were observed in 13 patients: 11 patients with two unrelated clones, one patient with three unrelated clones, and one patient with four unrelated clones. Twelve cases of unrelated clones presented as t-MDS, whereas only one case presented as overt t-AML. Partial or complete deletions of the long arms or monosomy for chromosome 5 or chromosome 7, which are characteristic of t-MDS and t-AML, were observed in both unrelated clones in four patients and in one unrelated clone only in six patients, whereas three patients showed aberrations in both clones that were uncharacteristic of t-MDS or t-AML. Three different interpretations of the origin and significance of cytogenetically unrelated clones in t-MDS and t-AML are presented, although the disease is still considered to be monoclonal. First, patients with different defects of the long arm of chromosome 5 or chromosome 7 in two unrelated clones often seem to have acquired these aberrations as independent events. For this reason, it is possible that they may play an important role in leukemic transformation, for instance, by activating or potentiating the effect of a genetic change that is present in all cells but not disclosed as a visible chromosome abnormality. In cases with involvement of other chromosomes, unrelated clones sometimes develop by cytogenetic change in only a subclone of cells, indicating that they play a role only in tumor progression. Finally, unrelated clones in t-MDS and t-AML may represent two different monoclonal diseases: the primary tumor and t-MDS. This view is supported by the significant excess of unrelated clones observed in t-MDS following multiple myeloma (4 in 13 cases) compared with other diseases (9 in 167 cases; P = 0.02), and by results from a case with a balanced translocation that is highly characteristic of non-Hodgkin's lymphoma in one clone and a t-MDS-associated deletion of the long arm of chromosome 5 in another.

Asunto(s)

Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Neoplasias Primarias Secundarias/genética , Adulto , Anciano , Anciano de 80 o más Años , Niño , Células Clonales , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Cariotipificación , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Neoplasias Primarias Secundarias/patología

RESUMEN

One hundred consecutive patients with malignant lymphoma treated with high-dose chemotherapy and autologous stem cell transplantation, followed at least 1 yr post-transplant, are reported, 68 with non-Hodgkin's lymphoma and 32 with Hodgkin's disease. At transplant, 23 patients were in first remission, 69 in later chemosensitive disease and 8 were chemotherapy resistant. Based on previous treatment and stem-cell source, the patients were subdivided into 3 cohorts: BMT1: bone-marrow harvest and transplant after > or =3 treatment regimens (38 patients); BMT2: bone marrow harvest and transplant after less than 3 treatment regimens (24 patients); PBSCT: peripheral-blood stem cell transplant (38 patients, 5 of these with CD34+ cell selected PBSC). The 4-yr survival and progression-free survival of all patients was 45 and 40%, respectively. Forty-one patients have died, 27 of lymphoma, evenly distributed in the cohorts. Fourteen treatment-related deaths occurred, 13 of these in the BMT1 cohort, significantly more than in the other cohorts (p=0.001). In univariate survival analysis cohort, age, disease status at transplant and number of previous treatment regimens were significant. In multivariate survival analysis cohort, age and sex were independently significant, women having a shorter survival. The patients transplanted with unselected PBSC had significantly shorter duration of pancytopenia and hospital stay than the otherwise comparable BMT2 patients, but their progression-free survival was identical. We confirm that high-dose therapy with autologous stem cell transplant from blood or bone marrow in not-too-heavily pretreated patients is a safe procedure but will cure only half the patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/terapia , Linfoma no Hodgkin/terapia , Adulto , Femenino , Supervivencia de Injerto , Movilización de Célula Madre Hematopoyética , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Trasplante Autólogo