Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Investigation of BMP6 mutations in Brazilian patients with iron overload.

BACKGROUND: Iron overload (IO) is a complex condition in which clinical, behavioral and genetic factors contribute to the phenotype. In multiethnic and non-Caucasian populations, mutations in HFE gene alone cannot explain IO in most of the cases, and additional genetic and environmental factors must be investigated. Bone Morphogenetic Proteins (BMPs) play a central role in iron homeostasis by modulating HAMP transcription through the signaling pathway that includes SMAD and HJV. In this study, we aimed to explore the clinical relevance of BMP6 mutations in a cohort of Brazilian patients with IO. METHODS: 41 patients with IO were evaluated. Blood samples were collected to analyze BMP6 mutations through New Sequence Generations (NGS). Frequency of variants and mutations were analyzed and correlated with clinical and environmental characteristics. RESULTS: We identified BMP6 mutations in three patients with IO. The p.Arg257His mutation was identified in two patients and the p.Leu71Val mutation was identified in one patient. Two of these patients had additional risk factors for IO (HFE mutations and diabetes mellitus). CONCLUSION: BMP6 mutations, when combined to other genetic and clinical risk factors, may contribute to IO. Functional studies and THE evaluation of large cohorts are necessary to fully address BMP6 role in IO.

The hemibiotrophic cacao pathogen Moniliophthora perniciosa depends on a mitochondrial alternative oxidase for biotrophic development.

The tropical pathogen Moniliophthora perniciosa causes witches' broom disease in cacao. As a hemibiotrophic fungus, it initially colonizes the living host tissues (biotrophic phase), and later grows over the dead plant (necrotrophic phase). Little is known about the mechanisms that promote these distinct fungal phases or mediate the transition between them. An alternative oxidase gene (Mp-aox) was identified in the M. perniciosa genome and its expression was analyzed througout the fungal life cycle. In addition, the effects of inhibitors of the cytochrome-dependent respiratory chain (CRC) and alternative oxidase (AOX) were evaluated on the in vitro development of M. perniciosa. Larger numbers of Mp-aox transcripts were observed in the biotrophic hyphae, which accordingly showed elevated sensitivity to AOX inhibitors. More importantly, the inhibition of CRC prevented the transition from the biotrophic to the necrotrophic phase, and the combined use of a CRC and AOX inhibitor completely halted fungal growth. On the basis of these results, a novel mechanism is presented in which AOX plays a role in the biotrophic development of M. perniciosa and regulates the transition to its necrotrophic stage. Strikingly, this model correlates well with the infection strategy of animal pathogens, particularly Trypanosoma brucei, which uses AOX as a strategy for pathogenicity.