Alteraciones epigenéticas en leucemia linfoblástica aguda

La leucemia linfoblástica aguda (LLA) es el tipo de cáncer más frecuente en niños. Aunque se sabe que las alteraciones genéticas constituyen la base de la etiología de la LLA, se ha demostrado que no son suficientes para el desarrollo leucémico; son necesarias alteraciones adicionales, como las modificaciones epigenéticas. En la LLA se han identificado alteraciones de este tipo, como la metilación del DNA, la modificación de histonas y la regulación por RNAs no codificantes. La hipermetilación del DNA en regiones promotoras es una de las alteraciones epigenéticas más frecuentes en LLA: y conlleva al silenciamiento de genes que generalmente son supresores de tumor y, en consecuencia, contribuye a la leucemogénesis. También se han detectado alteraciones en proteínas remodeladoras de histonas, como la sobreexpresión de enzimas desacetilasas de histonas, así como alteraciones en enzimas acetil transferasas y metil transferasas. En la LLA también se altera la expresión de miRNAs, lo cual produce desregulación en la expresión de sus genes blanco. Estas modificaciones epigenéticas son eventos clave en la transformación maligna, e involucran la desregulación de oncogenes como BLK, WNT5B y WISP1 y de supresores de tumor como FHIT, CDKN2A, CDKN2B y TP73, lo que afecta diversos procesos celulares fundamentales que conllevan al desarrollo de LLA. Las alteraciones epigenéticas y genéticas contribuyen en conjunto al desarrollo y evolución de la LLA

Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro

The evidence supporting the biological plausibility of the association of permethrin and malathion with hematological cancer is limited and contradictory; thus, further studies are needed. This study aimed to investigate whether in vitro exposure to 0.1 μM permethrin and malathion at 0, 24, 48 and 72 h after cell culture initiation induced changes in the gene expression and DNA methylation in mononuclear cells from bone marrow and peripheral blood (BMMCs, PBMCs). Both pesticides induced several gene expression modifications in both tissues. Through gene ontology analysis, we found that permethrin deregulates ion channels in PBMCs and BMMCs and that malathion alters genes coding proteins with nucleic acid binding capacity, which was also observed in PBMCs exposed to permethrin. Additionally, we found that both insecticides deregulate genes coding proteins with chemotaxis functions, ion channels, and cytokines. Several genes deregulated in this study are potentially associated with cancer onset and development, and some of them have been reported to be deregulated in hematological cancer. We found that permethrin does not induce DNA hypermethylation but can induce hypomethylation, and that malathion generated both types of events. Our results suggest that these pesticides have the potential to modify gene expression through changes in promoter DNA methylation and potentially through other mechanisms that should be investigated

Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

<div><p>Expression of the 6 and 8 dominant-negative Ikaros isoforms in pediatric patients with acute lymphoblastic leukemia has been associated with a high risk of relapse and death; due to these isoforms disrupting the differentiation and proliferation of lymphoid cells. The aim of this study was to know the frequency of Ik6 and Ik8 in 113 Mexican ALL-children treated within the National Popular Medical Insurance Program to determine whether there was an association with relapse-free survival, event-free survival and overall survival, and to assess its usefulness in the initial stratification of patients. The expression of these isoforms was analyzed using specific primer sets and nested RT-PCR. The detected transcripts were classified according to the isoforms’s sizes reported. A non-expected band of 300 bp from one patient was analyzed by sequencing. Twenty-six patients expressed Ik6 and/or Ik8 and one of them expressed a variant of Ik8 denominated Ik8-deleted. Although the presence of them was not statistically associated with lower relapse free survival (<i>p</i> = 0.432), event free survival (<i>p</i> = 0.667) or overall survival (<i>p</i> = 0.531), inferior overall survival was observed in patients that expressed these isoforms and showed high or standard risk by age and white blood-cell count at diagnosis. Of the 26 patients Ik6+ and/or Ik8+, 14 did not present adverse events; from them 6 were exclusively Ik6+ and/or Ik8+, and 8 were positive for the other Ikaros isoforms (Ik1, Ik2, Ik5, Ik3A, Ik4, Ik4A, Ik7). In the patients studied, the expression of Ik6 and Ik8 did not constitute an independent prognostic factor for relapse or death related to disease; therefore, they could not be used in the initial risk stratification.</p></div

Risk analysis for clinical-biological characteristics and dominant-negative Ikaros isoforms expression.

<p><i>p</i> = Analyzed by Fisher exact test.</p><p>* = Statistically significant <i>p</i> value.</p><p>Risk analysis for clinical-biological characteristics and dominant-negative Ikaros isoforms expression.</p

Clinical-biological characteristics and Ikaros isoforms expression in ALL children and their association with relapse, death or prednisone response.

<p><i>p</i> = Analyzed by Fisher exact test.</p><p>* = Statistically significant <i>p</i> value.</p><p>Clinical-biological characteristics and Ikaros isoforms expression in ALL children and their association with relapse, death or prednisone response.</p