Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5 T1562C, tandem-repeat ASNS polymorphism, derived haplotype, and ASS1 G1343T and G34T substitutions (P < .03). Associations were limited to patients who received Escherichia coli asparaginase. Variations that sustained correction for multiple testing (ATF5 T1562C, P ؍ .005; ASNS tandem-repeat and related haplotype, P < .01) were subsequently analyzed in the replication cohort. The E colidependent association of the ATF5 T1562 allele with reduced EFS was confirmed (P ؍ .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P < .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P < . IntroductionAcute lymphoblastic leukemia (ALL) is the most frequent malignancy of childhood. The introduction of multiagent treatment protocols has led to a remarkable increase in overall survival (OS) and event-free survival (EFS). Nevertheless, for a subpopulation of patients, resistance to the chemotherapeutics used within these protocols remains an obstacle to successful treatment. Asparaginase is a standard component in the therapy of childhood ALL. 1 Asparagine is required by all cells for survival and is normally produced by the enzyme asparagine synthethase (ASNS). Malignant lymphoblasts are thought to have low ASNS levels and therefore to depend on extracellular sources of asparagine for their rapid growth. Depletion of asparagine by asparaginase selectively kills leukemia cells by decreasing protein biosynthesis. 2 A significant improvement in OS and EFS was seen for children with ALL who were assigned to receive asparaginase during postremission consolidation compared with those who did not receive asparaginase. 3 Associations between treatment outcome and asparaginase dose intensity 4 and between an inferior outcome and the use of asparaginase preparation with a shorter half-life 5 have been reported. Asparaginase intolerance can manifest as allergic reactions, pancreatitis, and abnormalities of hemostasis. 6,7 Such asparaginaseassociated complications may also affect treatment outcomes. Patients who experienced a dose-limiting asparaginase toxicity had a significantly worse disease-free survival than those who were able to tolerate their intended doses. 4,5 The polymorphisms of the genes mediating asparaginase antileukemia effect can underlie observed variability. ...
In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.
Accurate methods are required for estimating the incidence of AIHA in children. Capture-recapture analysis corrects underreporting and provides optimal completeness. This study highlights a possible under diagnosis of this potentially severe disease in various pediatric settings. AIHA incidence may now be compared with the incidences of other hematological diseases and used for clinical or research purposes.
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