ITPA Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia.

Background: 6-Mercaptopurine (6-MP), a thiopurine agent, is a essential medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. Methods: This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. Results: The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wild-type ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wild-type ITPA (P = 0.016). Conclusions: HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wild-type ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.

Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome.

Shwachman-Diamond syndrome (SDS) is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with SDS contain mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS), encoding a highly conserved protein that has been implicated in ribosome biogenesis. Emerging evidence also suggests a distinct role of SBDS beyond protein translation. Using the yeast model of SDS, we examined the underlying mechanisms that cause cells lacking Sdo1p, the yeast SBDS ortholog, to exhibit reduced tolerance to various stress conditions. Our analysis indicates that the environmental stress response (ESR), heat shock response (HSR), and endoplasmic reticulum unfolded protein response (UPR) of sdo1Δ cells are functional and that defects in these pathways do not produce the phenotypes observed in sdo1Δ yeast. Depletion of mitochondrial DNA (mtDNA) was observed in sdo1Δ cells, and this is a probable cause of the mitochondrial insufficiency in SDS. Prior disruption of POR1, encoding the mitochondrial voltage dependent anion channel (VDAC), abrogated the effects of SDO1 deletion and substantially restored resistance to environmental stressors and protected against damage to mtDNA. Conversely, wild-type cells over-expressing POR1 exhibited growth impairment and increased stress sensitivity similar to that seen in sdo1Δ cells. Overall, our results suggest that specific VDAC inhibitors may have therapeutic benefits for SDS patients.