Evaluating the economic burden of acute myeloid leukemia in Canada.

Background Acute myeloid leukemia (AML) represents a significant burden for patients and their families, and to the healthcare system. This study estimated the total cost of illness associated with newly diagnosed AML patients in Canada. Methods The economic burden of AML was estimated using an incidence-based model, analyzing different types of AML cases in Canada. Direct and indirect costs were calculated using scientific literature and Canadian clinical experts' inputs. Patients were categorized depending on their eligibility for intensive chemotherapy (fit and unfit patients) as well as according to age and cytogenetic markers. Results The total average cost of AML per patient is estimated to be $178,073 with a cost of $210,983 and $145,163 for fit and unfit patients, respectively. The costs related to treatment represent half of the total average cost (52%), followed by hematopoietic stem cell transplant (23%), best supportive care (16%), productivity loss (6%) and wastage (4%) Conclusions For patients with AML, the costs associated with fit patients are higher than unfit patients. Hospitalization and best supportive care costs are key cost drivers for the total costs of fit and unfit patients, respectively. This study highlights that AML is associated with a significant economic burden in Canada.

Minireview: What is Known about SUMOylation Among NR4A Family Members?

NR4A receptors, including NUR77 (NR4A1), NURR1 (NR4A2) and NOR-1 (NR4A3), form a family of nuclear receptors that act as transcription factors to regulate many physiological and pathological processes such as cell cycle and apoptosis, lipid metabolism, inflammation, carcinogenesis, vascular and neuronal functions. In the absence of known endogenous ligand modulating their physiological functions, the NR4A family remains a class of orphan receptors. However, several post-translational modifications (PTMs), including SUMOylation, have been shown to regulate the expression and/or activity of these receptors. Addition of Small Ubiquitin-like MOdifier (SUMO) proteins is a dynamic and reversible enzymatic process that regulates multiple essential functions of proteins, including nuclear receptors. This review aims at summarizing what is known about the impact of SUMOylation on NR4A family member transcriptional activities and physiological functions.

Complex regulation of orphan nuclear receptor Nur77 (Nr4a1) transcriptional activity by SUMO2 and PIASγ.

Nur77 (NGFI-B) is a nuclear receptor that belongs to the Nr4a family of orphan nuclear receptors (Nr4a1). This transcription factor has been implicated in the regulation of multiple functions, such as cell cycle regulation, apoptosis, inflammation, glucose and lipid metabolism, and brain function. However, the mechanisms involved in its different regulatory properties remain unclear. In search for regulatory mechanisms of Nur77 function, we identified that Protein Inhibitor of Activated STAT gamma (PIASγ), an E3 SUMO-protein ligase, potently repressed Nur77 transcriptional activity in HEK-293T cells. This PIASγ activity was sensitive to Sentrin SUMO-specific protease 1 (SENP1). Substitution of two putative phylogenetically well-conserved small ubiquitin-like modifier (SUMO) acceptor sites, lysine 102 (K102) and 577 (K577) by arginine residues (R) modulated Nur77 transcriptional activity. In particular, Nur77-K102R and Nur77-K102R/K577R mutants strongly decreased the transcriptional activity of Nur77, whereas single K577R substitution increased transcriptional activity of Nur77. Repression of Nur77 transcriptional activity by SUMO2 and PIASγ was reduced by the K577R mutation, whereas the K102R mutant remained insensitive to SUMO2. Interestingly, the roles of these SUMO acceptor sites in Nur77 are distinct from previously observed activities on its close homolog Nurr1. Thus, the present study identified SUMO2 and PIASγ as important transcriptional co-regulators of Nur77.

Altered regulation of Nur77 nuclear receptor gene expression in the mesocorticolimbic regions of rat brain by amphetamine sensitization.

The mechanisms underlying psychostimulant drug-induced sensitization include long-term cellular and molecular adaptations in dopaminergic circuits. Nur77, a member of the Nur family of transcription factors, is expressed in brain regions receiving dopamine inputs and plays a role in activity-induced synaptic modification. Here we evaluated changes in Nur77 mRNA levels in the medial prefrontal cortex (mPFC), dorsal striatum (Str) and nucleus accumbens (NAc) of rats receiving a repeated, sensitizing regimen of amphetamine (AMPH). Results were compared to two groups of controls - animals receiving repeated injections of saline (Rp-SAL) or with no treatment (CON). Two weeks after the last injection, the effect of an acute challenge dose of AMPH on Nur77 expression was evaluated using in-situ hybridization. Repeated AMPH treatment (Rp-AMPH) increased the levels of Nur77 mRNA in the mPFC, NAc core and shell regions. However, the effects of an acute injection of AMPH in each of the three groups of animals was distinct. Whereas an acute AMPH led to a significant increase of Nur77 in all brain regions of the CON animals, it had no significant effect in Rp-SAL animals. Interestingly, in acute AMPH-injected Rp-AMPH animals, Nur77 mRNA levels in the mPFC, Str and NAc regions were significantly lower compared to CON and Rp-SAL animals treated with acute AMPH. There was a positive correlation between AMPH -induced locomotor activity and Nur77 mRNA expression in CON animals; however, this relationship was absent in Rp-SAL and Rp-AMPH animals. The data suggest that Nur77 is a part of neuroadaptive changes caused by either mild stress of repeated injections as well as AMPH-sensitization and may play a role in abnormal behaviors induced by the drug.