Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia.

Asparaginase, which depletes asparagine and glutamine, activates amino-acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered as a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this single-nucleotide polymorphism (SNP) are needed to develop therapeutic approaches that mitigate this toxicity.

Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.

Excessive collagen accumulation in dystrophic (mdx) respiratory musculature is independent of enhanced activation of the NF-kappaB pathway.

Skeletal muscle fibrosis is present in the diaphragm of the mdx mouse, a model for Duchenne dystrophy. In both the mouse and human, dystrophic muscle exhibits pronounced increases in NF-kappa B signaling. Various inhibitors of this pathway, such as pyrrolidine dithiocarbamate (PDTC) and ursodeoxycholic acid (UDCA), have been shown to have beneficial effects on dystrophic (mdx) muscle. The present study characterizes the development of fibrosis in the mdx musculature, and determines the fibrolytic efficacy of PDTC and UDCA. The results indicate that collagen accumulation and the expression of fibrogenic (TGF-beta1) and fibrolytic (MMP-9) mediators are dependent on muscle origin in both nondystrophic and mdx mice. Excessive collagen accumulation is observed in the mdx respiratory musculature prior to substantial muscle degeneration and cellular infiltration, and is associated with dystrophic increases in the expression of TGF-beta1 with no corresponding increases in MMP-9 expression. Treatment with PDTC or UDCA did not influence collagen deposition or TGF-beta1 expression in the mdx respiratory musculature. These results indicate that dystrophic increases in collagen are the result of NF-kappaB-independent signaling abnormalities, and that efforts to reduce excessive collagen accumulation will require treatments to more specifically reduce TGF-beta1 signaling or enhance the expression and/or activity of matrix metalloproteases.