-
Leukemia Jan 2024In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3...
Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study.
In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.
Topics: Humans; Aged; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Nitriles; Quinolines; Comorbidity; Antineoplastic Agents; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 38007586
DOI: 10.1038/s41375-023-02080-y -
Communications Biology Aug 2023Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6...
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10, we confirmed association of the FADS signal and found evidence of two additional signals (in DAGLA and BEST1) within 200 kb of the originally reported FADS signal. Outside of the FADS region, we identified novel signals for arachidonic acid (AA) in Hispanic Americans located in/near genes including TMX2, SLC29A2, ANKRD13D and POLD4, and spanning a > 9 Mb region on chromosome 11 (57.5 Mb ~ 67.1 Mb). Among these novel signals, we found associations unique to Hispanic Americans, including rs28364240, a POLD4 missense variant for AA that is common in CHARGE Hispanic Americans but absent in other race/ancestry groups. Our study sheds light on the genetics of PUFAs and the value of investigating complex trait genetics across diverse ancestry populations.
Topics: Humans; Genome-Wide Association Study; Fatty Acids, Omega-6; Black or African American; Genomics; Hispanic or Latino; Bestrophins
PubMed: 37587153
DOI: 10.1038/s42003-023-05219-w -
Cancers Apr 2024Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis.... (Review)
Review
Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.
PubMed: 38730657
DOI: 10.3390/cancers16091705 -
Frequency and Prognostic Impact of Aberrant Antigens Expression among Egyptian Adult Acute Leukemia.Asian Pacific Journal of Cancer... Dec 2023Aberrant antigen expression was reported to be due to genetic and epigenetic dysregulation. This study aimed to address aberrant antigen expression and its link to poor...
OBJECTIVE
Aberrant antigen expression was reported to be due to genetic and epigenetic dysregulation. This study aimed to address aberrant antigen expression and its link to poor prognostic genetic markers in acute leukemia patients.
METHODS
This study included 432 newly diagnosed acute leukemia patients (AML, B-ALL). For all included patients blast cells expression for line assignment CD33 CD13 on B-All and CD7 on cytogenetically normal-AML blasts was assessed by flow cytometry in parallel to FLT3 and Philadelphia and philadelphia like chromosome in B-ALL.
RESULTS
From the total 432 cases of acute leukemia, the most frequent aberrant antigen expressed in B acute lymphoid leukemia (ALL) was CD33 (23.3%) followed by CD13(16.7%); while the most frequent one in AML was CD7 (16.7%). Aberrant myeloid phenotype in B-ALL was associated with lower mean total leukocytes count (TLC), low platelets count, positive Philadelphia like chromosome, shorter overall survival compared to the B-ALL without. Aberrant lymphoid phenotype (CD7) in AML was associated with a higher platelets count, FLT3 mutation, shorter disease-free and overall survival compared to those patients without.
CONCLUSION
CD7 aberrant antigen expression is frequently detected in patients with CN-AML and frequently associated with FLT3 mutation. While in patients with B-ALL the most frequently detected ones are CD33 and CD13 which are frequently associated with Philadelphia like chromosome.
Topics: Adult; Humans; Antigens, CD; Prognosis; Egypt; Leukemia, Myeloid, Acute; Antigens, CD7; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Immunophenotyping
PubMed: 38156867
DOI: 10.31557/APJCP.2023.24.12.4301 -
Haematologica Feb 2024Innovations in molecular diagnostics have often evolved through the study of hematologic malignancies. Examples include the pioneering characterization of the... (Review)
Review
Innovations in molecular diagnostics have often evolved through the study of hematologic malignancies. Examples include the pioneering characterization of the Philadelphia chromosome by cytogenetics in the 1970s, the implementation of polymerase chain reaction for high-sensitivity detection and monitoring of mutations and, most recently, targeted next- generation sequencing to drive the prognostic and therapeutic assessment of leukemia. Hematologists and hematopath- ologists have continued to advance in the past decade with new innovations improving the type, amount, and quality of data generated for each molecule of nucleic acid. In this review article, we touch on these new developments and discuss their implications for diagnostics in hematopoietic malignancies. We review advances in sequencing platforms and library preparation chemistry that can lead to faster turnaround times, novel sequencing techniques, the development of mobile laboratories with implications for worldwide benefits, the current status of sample types, improvements to quality and reference materials, bioinformatic pipelines, and the integration of machine learning and artificial intelligence into mol- ecular diagnostic tools for hematologic malignancies.
Topics: Humans; Artificial Intelligence; Mutation; Hematologic Neoplasms; Polymerase Chain Reaction; High-Throughput Nucleotide Sequencing
PubMed: 37584286
DOI: 10.3324/haematol.2022.282442 -
Science Advances Mar 2024Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the fusion gene, remains a poor prognosis cancer needing new therapeutic...
Philadelphia chromosome-positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the fusion gene, remains a poor prognosis cancer needing new therapeutic approaches. Transcriptomic profiling identified up-regulation of oncogenic transcription factors ERG and c-MYC in B-ALL with ERG and c-MYC required for B-ALL in murine and human models. Profiling of ERG- and c-MYC-dependent gene expression and analysis of ChIP-seq data established ERG and c-MYC coordinate a regulatory network in B-ALL that controls expression of genes involved in several biological processes. Prominent was control of ribosome biogenesis, including expression of RNA polymerase I (POL I) subunits, the importance of which was validated by inhibition of cells by POL I inhibitors, including CX-5461, that prevents promoter recruitment and transcription initiation by POL I. Our results reveal an essential ERG- and c-MYC-dependent transcriptional network involved in regulation of metabolic and ribosome biogenesis pathways in B-ALL, from which previously unidentified vulnerabilities and therapeutic targets may emerge.
Topics: Animals; Humans; Mice; Fusion Proteins, bcr-abl; Gene Regulatory Networks; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transcription Factors; Transcriptional Regulator ERG
PubMed: 38457494
DOI: 10.1126/sciadv.adj8803 -
European Journal of Case Reports in... 2023Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) that can effectively treat patients with acute lymphoblastic leukaemia (ALL), particularly those with...
UNLABELLED
Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) that can effectively treat patients with acute lymphoblastic leukaemia (ALL), particularly those with Philadelphia chromosome-positive (Ph+ALL) subtype, who are resistant or have previously received other TKIs. We report a case of a 42-year-old female with Ph+ALL who was admitted to the intensive care unit with respiratory failure and severe acute respiratory distress syndrome (ARDS), while on treatment with ponatinib. Despite being treated with multiple antibiotics and antivirals, the patient's condition continued to worsen, and pulmonary complications secondary to TKI were suspected. After starting a steroid regimen, the patient's condition improved drastically with resolution of the pulmonary complications. While many adverse events (AEs) happen in the beginning stages of TKI treatment, certain toxicities may not arise until months after therapy initiation. Cardiovascular complications are the most common AE of ponatinib, including heart failure and arterial hypertension. Pulmonary complications may occur, and management includes drug cessation and individualised steroid therapy. In case of respiratory failure without signs of infection and no improvement with antimicrobial treatment, clinicians should consider the possibility of pulmonary toxicity associated with ponatinib.
LEARNING POINTS
Although rarely reported, ponatinib may have pulmonary toxicity presenting as new onset of respiratory insufficiency.Management of pulmonary complications includes adjusting or discontinuation of ponatinib and simultaneous treatment with steroids.
PubMed: 38077703
DOI: 10.12890/2023_004162 -
BioRxiv : the Preprint Server For... Oct 2023The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the...
BACKGROUND
The X chromosome is often omitted in disease association studies despite containing thousands of genes which may provide insight into well-known sex differences in the risk of Alzheimer's Disease.
OBJECTIVE
To model the expression of X chromosome genes and evaluate their impact on Alzheimer's Disease risk in a sex-stratified manner.
METHODS
Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF>0.05) within the -regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome.
RESULTS
Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p 0.05, with only in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002).
CONCLUSIONS
We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, .
PubMed: 37333116
DOI: 10.1101/2023.06.06.543877 -
BioRxiv : the Preprint Server For... Jul 2023The physical basis of phase separation is thought to consist of the same types of bonds that specify conventional macromolecular interactions yet is unsatisfyingly often...
The physical basis of phase separation is thought to consist of the same types of bonds that specify conventional macromolecular interactions yet is unsatisfyingly often referred to as 'fuzzy'. Gaining clarity on the biogenesis of membraneless cellular compartments is one of the most demanding challenges in biology. Here, we focus on the chromosome passenger complex (CPC), that forms a chromatin body that regulates chromosome segregation in mitosis. Within the three regulatory subunits of the CPC implicated in phase separation - a heterotrimer of INCENP, Survivin, and Borealin - we identify the contact regions formed upon droplet formation using hydrogen/deuterium-exchange mass spectrometry (HXMS). These contact regions correspond to some of the interfaces seen between individual heterotrimers within the crystal lattice they form. A major contribution comes from specific electrostatic interactions that can be broken and reversed through initial and compensatory mutagenesis, respectively. Our findings reveal structural insight for interactions driving liquid-liquid demixing of the CPC. Moreover, we establish HXMS as an approach to define the structural basis for phase separation.
PubMed: 37292983
DOI: 10.1101/2023.05.22.541822 -
MedRxiv : the Preprint Server For... Sep 2023Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between...
Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project.
Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near , , and significantly associated with AD (p < 5×10). Population-specific analyses identified a haplotype on chromosome 14 including associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5×10) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10), and rare noncoding variants in the promoter of distinct of in pooled-population analyses (p=7.2×10). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.
PubMed: 37693521
DOI: 10.1101/2023.09.01.23294953