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Leukemia Research Reports 2024T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a rare and aggressive leukemia. Philadelphia chromosome-positive cytogenetic abnormality is most common in...
A rare case of Philadelphia-positive (P210BCR-ABL1) T-cell acute lymphoblastic leukemia/lymphoma associated with minimal residual disease persistence after intensive chemotherapeutic approaches.
T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a rare and aggressive leukemia. Philadelphia chromosome-positive cytogenetic abnormality is most common in CML. It is difficult to differentiate between de novo Ph+ T-ALL/LBL and T-cell lymphoblastic crises of CML. We present a case of adult Ph+ T-ALL/LBL with a likely history of antecedent CML. Initially thought to be a case of chronic-phase CML, a diagnostic quandary led to the pursuit of a lymph node biopsy that established the diagnosis of Ph+ T-LBL or T lymphoblastic blast crisis of CML, a clinical presentation extremely rare and only the second of its kind from our review of the literature. The patient was treated with an intensive chemotherapy regimen for over a year due to persistent minimal residual disease (MRD) positivity indicating aggressive disease.
PubMed: 38572397
DOI: 10.1016/j.lrr.2024.100456 -
Journal of Pediatric Genetics Mar 2024encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of is associated with a neurodevelopmental disorder:...
encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of is associated with a neurodevelopmental disorder: autosomal dominant mental retardation with language impairment with or without autistic features. More recently, heterozygous variants have also been shown to cause a variety of structural birth defects including central nervous system (CNS) anomalies, congenital heart defects, congenital anomalies of the kidney and urinary tract, cryptorchidism, and hypospadias. In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion. Based on this deletion, and deletions previously reported in two other individuals with CDH, we define a CDH critical region on chromosome 3p13 that includes and four other protein-coding genes. We also provide detailed clinical descriptions of two previously reported individuals with CDH who carry de novo, pathogenic variants in that are predicted to trigger nonsense-mediated mRNA decay. A subset of individuals with putatively deleterious variants has also been shown to develop CDH. Since FOXP proteins function as homo- or heterodimers and the homologs of and are expressed at the same time points in the embryonic mouse diaphragm, they may function together as a dimer, or in parallel as homodimers, to regulate gene expression during diaphragm development. Not all individuals with heterozygous, loss-of-function changes in develop CDH. Hence, we conclude that acts as a susceptibility factor that contributes to the development of CDH in conjunction with other genetic, epigenetic, environmental, and/or stochastic factors.
PubMed: 38567173
DOI: 10.1055/s-0043-1767731 -
HemaSphere Apr 2024
PubMed: 38566805
DOI: 10.1002/hem3.67 -
PLoS Pathogens Apr 2024Lyme disease is a tick-borne infection caused by the spirochete Borrelia (Borreliella) burgdorferi. Borrelia species have highly fragmented genomes composed of a linear...
Lyme disease is a tick-borne infection caused by the spirochete Borrelia (Borreliella) burgdorferi. Borrelia species have highly fragmented genomes composed of a linear chromosome and a constellation of linear and circular plasmids some of which are required throughout the enzootic cycle. Included in this plasmid repertoire by almost all Lyme disease spirochetes are the 32-kb circular plasmid cp32 prophages that are capable of lytic replication to produce infectious virions called ϕBB-1. While the B. burgdorferi genome contains evidence of horizontal transfer, the mechanisms of gene transfer between strains remain unclear. While we know that ϕBB-1 transduces cp32 and shuttle vector DNA during in vitro cultivation, the extent of ϕBB-1 DNA transfer is not clear. Herein, we use proteomics and long-read sequencing to further characterize ϕBB-1 virions. Our studies identified the cp32 pac region and revealed that ϕBB-1 packages linear cp32s via a headful mechanism with preferential packaging of plasmids containing the cp32 pac region. Additionally, we find ϕBB-1 packages fragments of the linear chromosome and full-length plasmids including lp54, cp26, and others. Furthermore, sequencing of ϕBB-1 packaged DNA allowed us to resolve the covalently closed hairpin telomeres for the linear B. burgdorferi chromosome and most linear plasmids in strain CA-11.2A. Collectively, our results shed light on the biology of the ubiquitous ϕBB-1 phage and further implicates ϕBB-1 in the generalized transduction of diverse genes and the maintenance of genetic diversity in Lyme disease spirochetes.
Topics: Humans; Borrelia burgdorferi; Bacteriophages; Plasmids; Lyme Disease; Genomics; DNA
PubMed: 38558079
DOI: 10.1371/journal.ppat.1012122 -
International Heart Journal 2024Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or...
Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.
Topics: Humans; Coronary Vasospasm; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Imidazoles; Pyridazines
PubMed: 38556342
DOI: 10.1536/ihj.23-355 -
JAMA Network Open Mar 2024The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL)....
IMPORTANCE
The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry.
OBJECTIVES
To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023.
EXPOSURE
Genomic identification of an additional X or Y chromosome.
MAIN OUTCOMES AND MEASURES
Outcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio.
RESULTS
Of 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]).
CONCLUSION AND RELEVANCE
In this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.
Topics: Male; Humans; Female; Veterans; Prevalence; Case-Control Studies; Cross-Sectional Studies; Quality of Life; Sex Chromosome Aberrations; Aneuploidy; Morbidity; Sex Chromosomes; XYY Karyotype; Sex Chromosome Disorders
PubMed: 38551561
DOI: 10.1001/jamanetworkopen.2024.4113 -
Case Reports in Hematology 2024Evidence suggests that the earliest genetic events in the evolution of a cancer can predate diagnosis by several years or decades. In chronic myeloid leukemia (CML), the...
Evidence suggests that the earliest genetic events in the evolution of a cancer can predate diagnosis by several years or decades. In chronic myeloid leukemia (CML), the BCR::ABL1 fusion driver mutation can be present for an extended period before clinical disease manifests. The time between the BCR::ABL1 occurrence and symptom onset is referred to as the latency period. Though modeling studies predict this latency period is no more than ten years, it is still unclear how long it can be. We present a case of a patient referred for suspected CML. Both karyotype and FISH analysis identified the (9;22)(34;11.2) translocation resulting in the Philadelphia chromosome formation in 98.5% of cells analyzed. The patient responded to imatinib and achieved a sustained complete hematologic and cytogenetic remission. Clinical history revealed that the same patient presented eight years previously with anemia. Various non-neoplastic conditions were excluded, and a bone marrow biopsy was performed to rule out MDS. Cytogenetic analysis at that time revealed del(20) as the sole abnormality in all 20 cells analyzed. No treatment was given since the presence of isolated del(20) is not considered evidence of MDS in the absence of diagnostic morphologic criteria. Retrospective FISH analysis of archived bone marrow pellets from this previous specimen revealed the presence of BCR::ABL1 in 1.8% of cells. A clonal population of cells harboring the BCR::ABL1 fusion was unambiguously detected in this patient's archived bone marrow pellet obtained eight years before the current CML diagnosis. This case demonstrates that Carnoy's fixed nuclear pellets stored in cytogenetic laboratories are suitable for detecting driver mutations years before disease presentation. Such archived material may be useful for the retrospective studies needed to better understand the initiation and subsequent development of hematological malignancies. By identifying individuals who are at increased risk, it may be possible to initiate preventive measures or begin treatment at an earlier stage before disease progression.
PubMed: 38550770
DOI: 10.1155/2024/2127657 -
World Journal of Oncology Apr 2024Asciminib is approved for treating patients with chronic-phase chronic myeloid leukemia who were previously treated with two or more tyrosine kinase inhibitors or those...
BACKGROUND
Asciminib is approved for treating patients with chronic-phase chronic myeloid leukemia who were previously treated with two or more tyrosine kinase inhibitors or those with mutation. However, the mechanisms underlying asciminib resistance remain unclear.
METHODS
In this study, we established a new asciminib-resistant cell line. We examined gene mutation analysis and the effects of conventional chronic myelogenous leukemia inhibitors.
RESULTS
Direct sequencing revealed and mutations in asciminib-resistant cells. Ponatinib and omacetaxine were effective against asciminib-resistant cells.
CONCLUSIONS
and mutations are extremely resistant to asciminib. Ponatinib and omacetaxine show potential for treating asciminib-resistant chronic myeloid leukemia.
PubMed: 38545482
DOI: 10.14740/wjon1818 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Older adults who are diagnosed with acute lymphoblastic leukemia (ALL) and are treated with chemotherapy generally have poor outcomes. Blinatumomab is a CD19/CD3...
Older adults who are diagnosed with acute lymphoblastic leukemia (ALL) and are treated with chemotherapy generally have poor outcomes. Blinatumomab is a CD19/CD3 bispecific T-cell engager that has been approved for the treatment of B-cell ALL in the relapsed/refractory setting or in patients with minimal residual disease (MRD) positivity. We previously reported on a small cohort of older adults with newly diagnosed Philadelphia chromosome negative B-cell ALL who were treated with blinatumomab monotherapy in the first line setting. This is a long-term follow up of those patients and their clinical courses. All five patients achieved complete remission (CR) after one cycle of blinatumomab, and three were MRD-negative. Two patients completed three cycles of blinatumomab, two patients completed four cycles of blinatumomab, and one patient completed 17 cycles of blinatumomab total. In the last four years, four of these patients had relapsed disease requiring additional therapy. Two patients are alive after 61 months and 57 months since their first cycle of blinatumomab. Two of the patients died at 10 months and one died at 20 months. Here we describe the long-term clinical courses of these patients.
PubMed: 38543121
DOI: 10.3390/ph17030335 -
Turkish Journal of Haematology :... May 2024
Topics: Humans; Janus Kinase 2; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Philadelphia Chromosome; Male; Mutation; Female
PubMed: 38528751
DOI: 10.4274/tjh.galenos.2024.2023.0467