RESUMEN
Ikaros is a zinc-finger transcriptional factor playing an essential role in lymphoid lineage commitment and differentiation. Animal models and analysis of human Ikaros in leukemic cells demonstrate deregulation of Ikaros expression. Short isoforms with a truncated DNA-binding domain suppress functions of Ikaros in a dominant-negative manner. Previous studies demonstrated that human leukemias are heterogeneous for Ikaros expression. We estimate the relative level of Ikaros mRNA transcripts in 80 childhood ALL cases in comparison with AML and healthy donor groups. We detected eight major isoforms and several minor mutant isoforms in most patients with acute lymphoblastic and myeloid leukemia and in healthy donors, but the relative level of expression varied. The relatively high level of Ik4A isoform, rarely mentioned in previous reports, was detected in all analyzed groups. The ratio between functional and all isoforms was used to determine functional activity of Ikaros. The ratio was significantly less in AML (p=0.027) and BCR-ABL positive ALL (p=0.0028) than in healthy bone marrow. We found a negative association between the Ikaros ratio and myeloid coexpression in B-cell ALL, the most prominent was for CD15. The Ikaros ratio positively correlates with CD5 and negatively with CD7 expression in T-ALL. We suggest that an anti-proliferation and anti-activation effect of full-length Ikaros may be mediated through regulation of CD5 and CD7.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Factor de Transcripción Ikaros/genética , Leucemia/genética , Adolescente , Línea Celular , Niño , Preescolar , Expresión Génica , Humanos , Factor de Transcripción Ikaros/metabolismo , Lactante , Recién Nacido , Proteínas Mutantes , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangement is conventionally used for assessment of lymphoid malignant cells. TCR genes rearrangements were reported to occur at high frequency in B-lineage acute lymphoblastic leukemia (ALL). Therefore, we have analyzed 83 children with acute B-lineage ALL (67 de novo patients and 19 relapses) by PCR analysis for clonal IgH, incomplete TCRD (Vdelta2-Ddelta3 and Ddelta2-Ddelta3) and TCRG rearrangements. It was shown that clonal cross-lineage TCR rearrangements were associated with more immature immunophenotype (CD34+, CD117+, CyIgM-) of leukemic cells from patients' bone marrow (BM) samples as compared to cell samples without cross-lineage TCR rearrangements. That was equally detected both in de novo and relapsed cases of disease. Low frequency of clonal TCRG rearrangements was associated with expression of E2A/PBX chimeric oncogene. We suggest that TCRG and TCRD clonal rearrangements in leukemic B-cells are associated with early stages of their differentiation.
Asunto(s)
Linfoma de Burkitt/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Fusión bcr-abl/genética , Proteínas de Homeodominio/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos de Linfocitos T/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Lactante , Masculino , Reacción en Cadena de la Polimerasa/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Recurrencia , Sensibilidad y EspecificidadRESUMEN
Aberrant expression of tumor suppressor genes WT 1, RB 1, p53, homozygous deletion of p16 gene and their relationship with expression of oncogenes BCR-ABL, TEL-AML 1, MLL-AF 4, E2A-PBX 1, SIL-TAL 1 were determined in bone marrow samples of children with de novo B-lineage (n=170) and T-lineage (n=25) acute lymphoblastic leukemia (ALL). In contrast to expression of chimeric oncogenes alterations in p16, WT 1, RB 1 and p53 expression were T/B-lineage-unrestricted. Significant association between expression of MLL-AF 4 and WT 1, E2A-PBX 1 and p53; SIL-TAL 1 and homozygous deletion of p16 has been demonstrated.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Oncogenes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Línea Celular Tumoral , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Eliminación de Gen , Genes de Retinoblastoma/genética , Genes del Tumor de Wilms , Genes p53/genética , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , PronósticoRESUMEN
BACKGROUND: This study was conducted to evaluate the significance of serum level of immunoglobulins (Igs) and particularly IgG for leukemic cell persistence in peripheral blood (PB) and prognosis for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: Human sera were obtained from 68 children with primary B-lineage ALL at diagnosis and 46 healthy children (control). Serum level of IgM, IgG, IgA, IgG1, IgG2, IgG3, IgG4, antitumor antibody, homogeneous IgG were quantified by turbidimetric or enzyme-linked immunosorbent assays. RESULTS: The mean values of serum IgM, IgG, IgA at diagnosis were not differed significantly in ALL patients and control children. The level of IgM and IgG1 inversely correlated with white blood cell (WBC) count in PB of patients. Normal range of serum IgG, separated by 25th and 75th percentiles of IgG variables, was associated in patients with decreased WBC count in PB but not in bone marrow (BM) versus patients with low concentration of IgG. Normal range of IgG also favors low frequency of homogeneous IgG and antitumor antibodies. Patients with high level of IgG, besides increased frequency of homogeneous IgG and antitumor antibodies, had worse 3-year overall survival (OS) rate as compared to patients with normal level of IgG (58.8 vs. 91.2%, P = 0.014). CONCLUSIONS: The normal level of serum IgG at diagnosis is a beneficial prognostic factor associated with lower rate of leukemic cell persistence in PB and better outcome of childhood B-lineage ALL.