Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.

Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.

Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia.

By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and ID1, BAALC, ERG, and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality (P < .001), remission (P = .004), overall survival (P < .001), cumulative incidence of relapse (P = .028), disease-free survival (P = .03), and event-free survival (P < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure.

Evaluation of the European LeukemiaNet recommendations for predicting outcomes of patients with acute myeloid leukemia treated in low- and middle-income countries (LMIC): A Brazilian experience.

BACKGROUND: Current results regarding treatment outcomes in acute myeloid leukemia (AML) point to significant differences between low- and middle-income countries (LMIC) and high-income countries (HIC). Excluding well-known socioeconomic issues, genetic markers important for prognosis have not been properly incorporated into the clinical practice so far and their usefulness outside of well-controlled clinical trials remain unknown. METHODS: Here, we assessed the clinical significance of the European LeukemiaNet (ELN) recommendations in 196 consecutive patients with AML in a real-life setting. All patients were younger than 60 years of age (49% male) and treated with conventional chemotherapy for induction and consolidation in three Brazilian Institutions that well represent Brazilian geographic and socioeconomic diversity. FINDINGS: Multivariable analysis showed that ELN recommendations had a slight association with complete remission achievement (odds ratio: 0.74, 95% confidence interval, CI: 0.53-1.01; P=0.06), but were independently associated with poor overall survival (OS) (hazard ratio, HR: 1.3, 95% CI: 1.1-1.54; P=0.002), disease-free survival (DFS) (HR: 1.42, 95% CI: 1.03-1.95; P=0.028) and event-free survival (EFS) (HR: 1.24, 95% CI: 1.06-1.47; P=0.007), considering initial leukocyte counts and age as confounders. ELN recommendations had no impact on cumulative incidence of relapse (P=0.09). INTERPRETATION: Our results suggest that within the context of LMIC, the prognostic markers recommended by ELN may be useful to predict patient's clinical outcomes; however, the OS, DFS and EFS were shorter than the reported in Europe and US for the respective risk groups.