The MLL (mixed-lineage leukemia) gene, located on chromosome 11q23, is involved in chromosomal translocations in a subtype of acute leukemia, which represents approximately 10% of acute lymphoblastic leukemia and 2.8% of acute myeloid leukemia cases. These translocations form fusions with various genes, of which more than 80 partner genes for MLL have been identified. The most recurrent fusion partner in MLL rearrangements (MLL-r) is AF4, mapping at chromosome 4q21, accounting for approximately 36% of MLL-r leukemia and particularly prevalent in MLL-r acute lymphoblastic leukemia (ALL) cases (57%). MLL-r leukemia is associated with a sudden onset, aggressive progression, and notoriously poor prognosis in comparison to non-MLL-r leukemias. Despite modern chemotherapeutic interventions and the use of hematopoietic stem cell transplantations, infants, children, and adults with MLL-r leukemia generally have poor prognosis and response to these treatments. Based on the frequency of patients who relapse, do not achieve complete remission, or have brief event-free survival, there is a clear clinical need for a new effective therapy. In this review, we outline the current therapy options for MLL-r patients and the potential application of CAR-T therapy.

Folic acid and its derivates, known as folates, are chemoprotective micronutrients of great interest because of their essential role in the maintenance of health and genomic integrity. The supplementation of folic acid during pregnancy has long been known to reduce the risk of neural tube defects (NTDs) in the foetus. Folate metabolism can be altered by many factors, including adequate intake through diet. Folate deficiency can compromise the synthesis, repair and methylation of DNA, with deleterious consequences on genomic stability and gene expression. These processes are known to be altered in chronic diseases, including cancer and cardiovascular diseases. This review focuses on the association between folate intake and the risk of childhood leukaemia. Having compiled and analysed studies from the literature, we show the documented effects of folates on the genome and their role in cancer prevention and progression with particular emphasis on DNA methylation modifications. These changes are of crucial importance during pregnancy, as maternal diet has a profound impact on the metabolic and physiological functions of the foetus and the susceptibility to disease in later life. Folate deficiency is capable of modifying the methylation status of certain genes at birth in both animals and humans, with potential pathogenic and tumorigenic effects on the progeny. Pre-existing genetic polymorphisms can modify the metabolic network of folates and influence the risk of cancer, including childhood leukaemias. The protective effects of folic acid might be dose dependent, as excessive folic acid could have the adverse effect of nourishing certain types of tumours. Overall, maternal folic acid supplementation before and during pregnancy seems to confer protection against the risk of childhood leukaemia in the offspring. The optimal folic acid requirements and supplementation doses need to be established, especially in conjunction with other vitamins in order to determine the most successful combinations of nutrients to maintain genomic health and wellbeing. Further research is therefore needed to uncover the role of maternal diet as a whole, as it represents a main factor capable of inducing permanent changes in the foetus.

The identification of clinically-relevant biomarkers is of upmost importance for the management of cancer, from diagnosis to treatment choices. We performed a pan-cancer analysis of the mitotic checkpoint budding uninhibited by benzimidazole 1 gene BUB1, in the attempt to ascertain its diagnostic and prognostic values, specifically in the context of drug response. BUB1 was found to be overexpressed in the majority of cancers, and particularly elevated in clinically aggressive molecular subtypes. Its expression was correlated with clinico-phenotypic features, notably tumour staging, size, invasion, hypoxia, and stemness. In terms of prognostic value, the expression of BUB1 bore differential clinical outcomes depending on the treatment administered in TCGA cancer cohorts, suggesting sensitivity or resistance, depending on the expression levels. We also integrated in vitro drug sensitivity data from public projects based on correlation between drug efficacy and BUB1 expression to produce a list of candidate compounds with differential responses according to BUB1 levels. Gene Ontology enrichment analyses revealed that BUB1 overexpression in cancer is associated with biological processes related to mitosis and chromosome segregation machinery, reflecting the mechanisms of action of drugs with a differential effect based on BUB1 expression.

The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.

Acute myeloid leukaemia (AML), typically a disease of elderly adults, affects 8 children per million each year, with the highest paediatric incidence in infants aged 0-2 of 18 per million. Recurrent cytogenetic abnormalities contribute to leukaemia pathogenesis, and are an important determinant of leukaemia classification. The t(7;12)(q36;p13) translocation is a high-risk AML subtype exclusively associated with infants, and represents the second most common abnormality in this age group. Mechanisms of t(7;12) leukaemogenesis remain poorly understood. The translocation relocates the entire MNX1 gene within the ETV6 locus, but a fusion transcript is present in only half of the patients and its significance is unclear. Instead, research has focused on ectopic MNX1 expression, a defining feature of t(7;12) leukaemia, which has nevertheless failed to produce transformation in conventional disease models. Recently, advances in genome editing technologies have made it possible to recreate the t(7;12) rearrangement at the chromosomal level. Together with recent studies of MNX1 involvement using murine in vivo, in vitro, and organoid-based leukaemia models, specific investigation on the biology of t(7;12) can provide new insights into this AML subtype. In this review, we provide a comprehensive up-to-date analysis of the biological features of t(7;12), and discuss recent advances in mechanistic understanding of the disease which may deliver much-needed therapeutic opportunities to a leukaemia of notoriously poor prognosis.

The last decade has seen significant progress in understanding how the genome is organized spatially within interphase nuclei. Recent analyses have confirmed earlier molecular cytogenetic studies on chromosome positioning within interphase nuclei and provided new information about the topologically associated domains (TADs). Examining the nuances of how genomes are organized within interphase nuclei will provide information fundamental to understanding gene regulation and expression in health and disease. Indeed, the radial spatial positioning of individual gene loci within nuclei has been associated with up- and down-regulation of specific genes, and disruption of normal genome organization within nuclei will result in compromised cellular health. In cancer cells, where reorganization of the nuclear architecture may occur in the presence of chromosomal rearrangements such as translocations, inversions, or deletions, gene repositioning can change their expression. To date, very few studies have focused on radial gene positioning and the correlation to gene expression in cancers. Further investigations would improve our understanding of the biological mechanisms at the basis of cancer and, in particular, in leukemia initiation and progression, especially in those cases where the molecular consequences of chromosomal rearrangements are still unclear. In this review, we summarize the main milestones in the field of genome organization in the nucleus and the alterations to this organization that can lead to cancer diseases.