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Cureus May 2024Acute lymphoblastic leukemia (ALL) is an uncommon and rapidly progressing blood cancer originating in the bone marrow, characterized by the abnormal proliferation of...
Acute lymphoblastic leukemia (ALL) is an uncommon and rapidly progressing blood cancer originating in the bone marrow, characterized by the abnormal proliferation of immature lymphocytes. Although most cases of ALL are observed in children, the disease pattern shows two peaks: one in early childhood and another around the age of 50. Approximately a fifth to a third of adults diagnosed with ALL exhibit cytogenetic abnormalities involving the Philadelphia chromosome. Despite the existence of several studies on Philadelphia chromosome-positive ALL (Ph+ ALL), our case accentuates the use of a multi-disciplinary approach to treatment and involves a patient from a unique demographic.
PubMed: 38903380
DOI: 10.7759/cureus.60679 -
Nature Communications Jun 2024DNA replication in differentiated cells follows a defined program, but when and how it is established during mammalian development is not known. Here we show using...
DNA replication in differentiated cells follows a defined program, but when and how it is established during mammalian development is not known. Here we show using single-cell sequencing, that late replicating regions are established in association with the B compartment and the nuclear lamina from the first cell cycle after fertilization on both maternal and paternal genomes. Late replicating regions contain a relative paucity of active origins and few but long genes and low G/C content. In both bovine and mouse embryos, replication timing patterns are established prior to embryonic genome activation. Chromosome breaks, which form spontaneously in bovine embryos at sites concordant with human embryos, preferentially locate to late replicating regions. In mice, late replicating regions show enhanced fragility due to a sparsity of dormant origins that can be activated under conditions of replication stress. This pattern predisposes regions with long neuronal genes to fragility and genetic change prior to separation of soma and germ cell lineages. Our studies show that the segregation of early and late replicating regions is among the first layers of genome organization established after fertilization.
Topics: Animals; DNA Replication; Mice; Embryo, Mammalian; Cattle; Nuclear Lamina; Female; Male; Humans; Embryonic Development; Genome; Single-Cell Analysis
PubMed: 38898078
DOI: 10.1038/s41467-024-49565-7 -
EJHaem Jun 2024A distinct subset of acute myeloid leukemia (AML) is characterized by the presence of the Philadelphia chromosome (Ph+), due to reciprocal translocation...
A distinct subset of acute myeloid leukemia (AML) is characterized by the presence of the Philadelphia chromosome (Ph+), due to reciprocal translocation t(9;22)(q34;q11.2). This chromosomal rearrangement leads to the fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL1 gene on chromosome 9, generating the fusion gene. The Ph+ AML subtype is associated with poor prognosis and resistance to conventional chemotherapy. Beyond the well-established fusion, recent studies have shed light on additional genetic abnormalities in Ph+ AML, including associations with rearrangements involving core binding factor beta (CBFB). We describe a case of de novo AML with concurrent and rearrangements.
PubMed: 38895060
DOI: 10.1002/jha2.895 -
Cancers May 2024The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach...
Ponatinib as a Prophylactic or Pre-Emptive Strategy to Prevent Cytological Relapse after Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Transplanted in Complete Cytological Remission.
The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5-6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2-63) after Allo-SCT ( = 0.01). The median starting dose of PONA was 30 mg/day (range 15-45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7-118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2-100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE.
PubMed: 38893226
DOI: 10.3390/cancers16112108 -
American Journal of Human Genetics Jun 2024Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms...
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10, OR = 1.27) and APOE (rs6857; p = 1.31 × 10, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
PubMed: 38889728
DOI: 10.1016/j.ajhg.2024.05.017 -
ELife Jun 2024Philadelphia chromosome-positive (Ph) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved...
Philadelphia chromosome-positive (Ph) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph leukemia.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; NEDD8 Protein; Ubiquitin-Protein Ligases; Muscle Proteins
PubMed: 38865175
DOI: 10.7554/eLife.88375 -
Cell Reports Jun 2024Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells...
Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.
PubMed: 38861385
DOI: 10.1016/j.celrep.2024.114323 -
Frontiers in Immunology 2024The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an...
INTRODUCTION
The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works.
MATERIALS AND METHODS
We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their V617F variant allele frequency ( = 24 in total).
RESULTS
The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively).
DISCUSSION
Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.
Topics: Nitriles; Humans; Pyrazoles; Pyrimidines; Myeloproliferative Disorders; Janus Kinase 2; Neoplastic Stem Cells; Models, Theoretical; Protein Kinase Inhibitors
PubMed: 38846951
DOI: 10.3389/fimmu.2024.1384509 -
Biology of Sex Differences Jun 2024Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated...
BACKGROUND
Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated with cardiovascular and cardiometabolic diseases, including inflammation, atherosclerosis, and type 2 diabetes. Testosterone replacement is beneficial or neutral to men's cardiovascular health. Testosterone deficiency is associated with cardiovascular events. Testosterone supplementation to hypogonadal men improves libido, increases muscle strength, and enhances mood. We hypothesized that sex chromosomes (XX and XY) interaction with testosterone plays a role in arterial stiffening.
METHODS
We used four core genotype male mice to understand the inherent contribution of sex hormones and sex chromosome complement in arterial stiffening. Age-matched mice were either gonadal intact or castrated at eight weeks plus an additional eight weeks to clear endogenous sex hormones. This was followed by assessing blood pressure, pulse wave velocity, echocardiography, and ex vivo passive vascular mechanics.
RESULTS
Arterial stiffening but not blood pressure was more significant in castrated than testes-intact mice independent of sex chromosome complement. Castrated mice showed a leftward shift in stress-strain curves and carotid wall thinning. Sex chromosome complement (XX) in the absence of testosterone increased collagen deposition in the aorta and Kdm6a gene expression.
CONCLUSION
Testosterone deprivation increases arterial stiffening and vascular wall remodeling. Castration increases Col1α1 in male mice with XX sex chromosome complement. Our study shows decreased aortic contractile genes in castrated mice with XX than XY sex chromosomes.
Topics: Animals; Male; Testosterone; Vascular Stiffness; Sex Chromosomes; Mice; Mice, Inbred C57BL; Blood Pressure; Orchiectomy
PubMed: 38845040
DOI: 10.1186/s13293-024-00624-0