Overcoming steroid resistance in T cell acute lymphoblastic leukemia

In a Perspective, Pieter Van Vlierberghe and Steven Goossens discuss Meijerink and colleagues' findings on steroid resistance in pediatric T cell acute lymphoblastic leukemia

Chemotherapy at the wheel of ALL relapse

In this issue of Blood, Li et al(1) present an extensive in-depth genetic characterization of diagnostic, relapse, and remission samples from a cohort of 103 pediatric patients with acute lymphoblastic leukemia (ALL) treated according to the Shanghai Children's Medical Center ALL-2005 frontline protocol. Together with data obtained from 208 serial bone marrow samples collected during ALL therapy, their work suggests that relapse in a fraction of childhood ALL patients is driven by chemotherapy-induced mutations, which impact therapy response

T-ALL and thymocytes : a message of noncoding RNAs

In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs. In this review, we give a detailed overview of the studies that describe the noncoding RNAome in T-ALL oncogenesis and normal T cell development

A novel and universal method for microRNA RT-qPCR data normalization

Gene expression analysis of microRNA molecules is becoming increasingly important. In this study we assess the use of the mean expression value of all expressed microRNAs in a given sample as a normalization factor for microRNA real-time quantitative PCR data and compare its performance to the currently adopted approach. We demonstrate that the mean expression value outperforms the current normalization strategy in terms of better reduction of technical variation and more accurate appreciation of biological changes

ParMap, an Algorithm for the Identification of Complex Genomic Variations in Nextgen Sequencing Data

Next-generation sequencing produces high-throughput data, albeit with greater error and shorter reads than traditional Sanger sequencing methods. This complicates the detection of genomic variations, especially, small insertions and deletions. Here we describe ParMap, a statistical algorithm for the identification of complex genetic variants using partially mapped reads in nextgen sequencing data. We also report ParMap’s successful application to the mutation analysis of chromosome X exome-captured leukemia DNA samples

Molecular-genetic insights in pediatric T-cell acute lymphoblastic leukemia

T-ALL is an aggressive T-cell malignancy with an inferior treatment outcome compared to B-lineage ALL. Intensive T-ALL research efforts during the last years lead to the identification of multiple genetic abnormalities that cooperate in the malignant transformation of thymocytes. Currently and in contrast to B-lineage ALL, genetic abnormalities are clinically not used for therapy stratification. Further progress on the treatment of T-ALL will require further genetic characterization, which will provide us with a better understanding of the pathogenesis of T-ALL and hopefully will lead to improved treatment schedules. As the general scope of this thesis, we performed genome-wide copy number analysis using array-CGH for the identification of novel genomic rearrangements in T-ALL that possibly relate to treatment outcome, i.e. prognostic factors, or provide further insight in the pathogenesis of T-cell leukemia

Xenopus tropicalis : joining the armada in the fight against blood cancer

Aquatic vertebrate organisms such as zebrafish have been used for over a decade to model different types of human cancer, including hematologic malignancies. However, the introduction of gene editing techniques such as CRISPR/Cas9 and TALEN, have now opened the road for other organisms featuring large externally developing embryos that are easily accessible. Thanks to its unique diploid genome that shows a high degree of synteny to the human, combined with its relatively short live cycle, Xenopus tropicalis has now emerged as an additional powerful aquatic model for studying human disease genes. Genome editing techniques are very simple and extremely efficient, permitting the fast and cheap generation of genetic models for human disease. Mosaic disruption of tumor suppressor genes allows the generation of highly penetrant and low latency cancer models. While models for solid human tumors have been recently generated, genetic models for hematologic malignancies are currently lacking for Xenopus. Here we describe our experimental pipeline, based on mosaic genome editing by CRISPR/Cas9, to generate innovative and high-performing leukemia models in X. tropicalis. These add to the existing models in zebrafish and will extend the experimental platform available in aquatic vertebrate organisms to contribute to the field of hematologic malignancies. This will extend our knowledge in the etiology of this cancer and assist the identification of molecular targets for therapeutic intervention