RESUMEN
BACKGROUND: The in vivo clinical significance of malignant stem cells remains unclear. METHODS: Patients who have the 5q deletion (del[5q]) myelodysplastic syndrome (interstitial deletions involving the long arm of chromosome 5) have complete clinical and cytogenetic remissions in response to lenalidomide treatment, but they often have relapse. To determine whether the persistence of rare but distinct malignant stem cells accounts for such relapses, we examined bone marrow specimens obtained from seven patients with the del(5q) myelodysplastic syndrome who became transfusion-independent while receiving lenalidomide treatment and entered cytogenetic remission. RESULTS: Virtually all CD34+, CD38+ progenitor cells and stem cells that were positive for CD34 and CD90, with undetectable or low CD38 (CD38−/low), had the 5q deletion before treatment. Although lenalidomide efficiently reduced these progenitors in patients in complete remission, a larger fraction of the minor, quiescent, CD34+,CD38-/low, CD90+ del(5q) stem cells as well as functionally defined del(5q) stem cells remained distinctly resistant to lenalidomide. Over time, lenalidomide resistance developed in most of the patients in partial and complete remission, with recurrence or expansion of the del(5q) clone and clinical and cytogenetic progression. CONCLUSIONS: In these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)
Asunto(s)
Antineoplásicos/farmacología , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Resistencia a Medicamentos/genética , Síndromes Mielodisplásicos/patología , Células Madre Neoplásicas/efectos de los fármacos , Talidomida/análogos & derivados , ADP-Ribosil Ciclasa 1/análisis , Anciano , Anciano de 80 o más Años , Antígenos CD34/análisis , Antineoplásicos/uso terapéutico , Femenino , Expresión Génica , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Células Madre Neoplásicas/inmunología , Fenotipo , Inducción de Remisión , Talidomida/farmacología , Talidomida/uso terapéutico , Antígenos Thy-1/análisisAsunto(s)
Antineoplásicos/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Secuencia de Bases , Técnicas de Cultivo de Célula/métodos , Aberraciones Cromosómicas , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Cariotipificación , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
Although it has been suggested that mutations of the FLT3, NRAS, KRAS, and PTPN11 genes are particularly frequent in high hyperdiploid (>50 chromosomes) pediatric acute lymphoblastic leukemias (ALLs), this has as yet not been confirmed in a large patient cohort. Furthermore, it is unknown whether mutations of these genes coexist in hyperdiploid cases. We performed mutation analyses of FLT3, NRAS, KRAS, and PTPN11 in a consecutive series of 78 high hyperdiploid ALLs. Twenty-six (33%) of the cases harbored a mutation, comprising six activating point mutations and one internal tandem duplication of FLT3 (7/78 cases; 9.0%), eight codon 12, 13, or 61 NRAS mutations (8/78 cases; 10%), five codon 12 or 13 KRAS mutations (5/78 cases, 6.4%), and seven exon 3 or 13 PTPN11 mutations (7/78 cases; 9.0%). No association was seen between the presence of a mutation in FLT3, NRAS, KRAS, or PTPN11 and gender, age, white blood cell count, or relapse, suggesting that they do not confer a negative prognostic impact. Only one case harbored mutations in two different genes, suggesting that mutations of these four genes are generally mutually exclusive. In total, one third of the cases harbored a FLT3, NRAS, KRAS, or PTPN11 mutation, identifying the RTK-RAS signaling pathway as a potential target for novel therapies of high hyperdiploid pediatric ALLs.
Asunto(s)
Diploidia , Genes ras , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas/genética , Tirosina Quinasa 3 Similar a fms/genética , Proteínas ras/genética , Adolescente , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Masculino , Proteínas Proto-Oncogénicas p21(ras)Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Antígenos CD/metabolismo , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 9/genética , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/metabolismo , Persona de Mediana Edad , Pronóstico , Factores de Transcripción/genéticaRESUMEN
The t(1;19)(q23;p13), which results in a fusion of TCF3 (previously E2A) at 19p13 with PBX1 at 1q23, is one of the most common translocations in acute lymphoblastic leukemia (ALL). It is seen either as a balanced t(1;19) or as an unbalanced der(19)t(1;19); occasional cases with coexisting t(1;19)- and der(19)-positive clones also have been described. Although it generally has been assumed that the unbalanced form arises from the balanced t(1;19) through loss of the derivative chromosome 1 followed by duplication of the normal homologue, this has never been proved. At least two other mechanisms are possible for the formation of the der(19): an initial trisomy 1 followed by translocation and subsequent loss of the der(1) or a rearrangement during the G2 phase of the cell cycle, with the derivative chromosomes 1 and 19 ending up in separate daughter cells. The different alternatives may be distinguished by investigation of markers proximal to the breakpoint in 1q23 because they would be expected to lead to different allelic patterns. Thus, loss of heterozygosity as a result of the presence of uniparental disomy (UPD)-both copies of a chromosome being derived from only one parent-for chromosome 1 would be present in all der(19)-harboring cases arising via the duplication pathway and in one-third of cases arising via the trisomy pathway, but in none of the der(19) formed via the G2 pathway. In this study, we used quantitative fluorescence PCR with polymorphic microsatellite markers to investigate chromosomes 1 and 19 in two t(1;19)- and four der(19)-positive ALLs. None of the der(19) cases displayed UPD for chromosome 1, excluding that this aberration arises through the duplication pathway. Because previous findings of cases with coexisting t(1;19) and der(19) clones are difficult to explain if the translocation originated in G2, the present results suggest that an unbalanced der(19) may arise from an initial trisomy 1 followed by t(1;19) translocation and loss of the derivative chromosome 1.