Hemoglobinopathies, namely β-thalassemia and sickle cell disease (SCD), are hereditary diseases, characterized by molecular genetic aberrations in the beta chains of hemoglobin. These defects affect the normal production of hemoglobin with severe anemia due to less or no amount of beta globins in patients with β-thalassemia (quantitative disorder), while SCD is a serious disease in which a mutated form of hemoglobin distorts the red blood cells into a crescent shape at low oxygen levels (qualitative disorder). Despite the revolutionary progress in recent years with the approval of gene therapy and gene editing for specific patients, there is an unmet need for highlighting the mechanisms influencing hemoglobin production and for the development of novel drugs and targeted therapies. The identification of the transcription factors and other genetic modifiers of hemoglobin expression is of utmost importance for discovering novel therapeutic approaches for patients with hemoglobinopathies. The aim of this review is to describe these complex molecular mechanisms and pathways affecting hemoglobin expression and to highlight the relevant investigational approaches or pharmaceutical interventions focusing on restoring the hemoglobin normal function by linking the molecular background of the disease with the clinical perspective. All the associated drugs increasing the hemoglobin expression in patients with hemoglobinopathies, along with gene therapy and gene editing, are also discussed.

The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML); the gene, located in the nucleolus, codes for a protein that normally shuttles between the nucleus and the cytoplasm of the normal hematopoietic cells. Patients harboring NPM1 mutations are diagnosed as having NPM1-mutated AMLs, which are types of leukemia with distinct clinical and laboratory characteristics. The essential diagnostics for investigating NPM1-mutated AMLs, the interactions with concomitant mutations affecting prognosis and the therapeutic interventions that the treatment of such patients requires are discussed in this review. Novel investigational agents in current clinical trials are also highlighted, along with the roles of exportin 1 (XPO1), menin-KMT2A inhibitors and immunotherapy in NPM1-mutated AMLs. This review focuses on critically evaluating the available data and aims to reveal the secrets of NPM1-mutated AMLs.