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Clinical Lymphoma, Myeloma & Leukemia Nov 2023The therapeutic landscape of Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) for adults has dramatically changed over the past 2 decades; the... (Review)
Review
The therapeutic landscape of Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) for adults has dramatically changed over the past 2 decades; the emergence of newer generations of tyrosine kinase inhibitors and incorporation of targeted immunotherapies into front-line therapy have significantly improved outcomes to the point where an argument can be made that this entity may no longer be considered a high-risk ALL subgroup. In this review article, we discuss different front-line regimens (both intensive and deintensified regimens including chemotherapy-free regimens). We also review disease monitoring strategies, discuss the role of allogeneic hematopoietic stem cell transplantation, and discuss the rapidly changing therapeutic landscape for patients with relapsed disease.
Topics: Humans; Adult; Protein Kinase Inhibitors; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation
PubMed: 37438208
DOI: 10.1016/j.clml.2023.06.007 -
American Journal of Hematology Aug 2023Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in...
Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long-term detectable BCR::ABL1 by PCR, six were PCR+/NGS-. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse-free survival and overall survival were similar in patients who were PCR+/NGS- and PCR-/NGS-, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS-based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low-level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.
Topics: Humans; Fusion Proteins, bcr-abl; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasm, Residual; High-Throughput Nucleotide Sequencing; Recurrence
PubMed: 37183966
DOI: 10.1002/ajh.26949 -
Molecular Microbiology May 2024The site-specific recombination pathway of bacteriophage λ encompasses isoenergetic but highly directional and tightly regulated integrative and excisive reactions that... (Review)
Review
The site-specific recombination pathway of bacteriophage λ encompasses isoenergetic but highly directional and tightly regulated integrative and excisive reactions that integrate and excise the vial chromosome into and out of the bacterial chromosome. The reactions require 240 bp of phage DNA and 21 bp of bacterial DNA comprising 16 protein binding sites that are differentially used in each pathway by the phage-encoded Int and Xis proteins and the host-encoded integration host factor and factor for inversion stimulation proteins. Structures of higher-order protein-DNA complexes of the four-way Holliday junction recombination intermediates provided clarifying insights into the mechanisms, directionality, and regulation of these two pathways, which are tightly linked to the physiology of the bacterial host cell. Here we review our current understanding of the mechanisms responsible for regulating and executing λ site-specific recombination, with an emphasis on key studies completed over the last decade.
Topics: Bacteriophage lambda; Recombination, Genetic; DNA, Viral; Viral Proteins; DNA, Bacterial; Binding Sites; Integration Host Factors
PubMed: 38372210
DOI: 10.1111/mmi.15241 -
Nature Aug 2023The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions. Although the molecular rules governing...
The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.
Topics: Humans; Chromatin; Chromosome Positioning; Chromosomes, Human; DNA; Genome, Human; Glycogen Synthase Kinases; High-Throughput Screening Assays; Interphase; Reproducibility of Results; RNA; Signal Transduction; Single-Cell Analysis; Cohesins
PubMed: 37438531
DOI: 10.1038/s41586-023-06340-w -
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 -
The Journal of Clinical Investigation Dec 2023Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study,...
Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.
Topics: Animals; Humans; Mice; Acetate-CoA Ligase; Fibrosis; Kidney; Kidney Diseases; Kidney Tubules; Lipogenesis
PubMed: 38051585
DOI: 10.1172/JCI172963 -
Frontiers in Oncology 2023Blinatumomab is a bispecific T cell engager that has shown efficacy in relapsed/refractory Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic... (Review)
Review
Blinatumomab is a bispecific T cell engager that has shown efficacy in relapsed/refractory Philadelphia chromosome (Ph)-positive and Ph-negative acute lymphoblastic leukemia (ALL). Considering its favorable safety and activity in advanced ALL, blinatumomab as a targeted immunotherapy is fast gaining a frontline position in the ALL treatment paradigm. There have been multiple completed and ongoing studies showing significant promise with improved response rates and survival outcomes and decreased treatment toxicity and need for multi-agent chemotherapy regimens. The early use of blinatumomab has established success in Ph-negative and Ph-positive B-ALL, and this has extended to older adults with ALL who have historically had substantially inferior outcomes compared to their pediatric and young adult counterparts. Herein we will review the current data describing the early use of blinatumomab in newly diagnosed adults with B-cell ALL and future directions.
PubMed: 37664035
DOI: 10.3389/fonc.2023.1237031 -
BioRxiv : the Preprint Server For... Jun 2023Large DNA assembly methodologies underlie milestone achievements in synthetic prokaryotic and budding yeast chromosomes. While budding yeast control chromosome...
Large DNA assembly methodologies underlie milestone achievements in synthetic prokaryotic and budding yeast chromosomes. While budding yeast control chromosome inheritance through ~125 bp DNA sequence-defined centromeres, mammals and many other eukaryotes use large, epigenetic centromeres. Harnessing centromere epigenetics permits human artificial chromosome (HAC) formation but is not sufficient to avoid rampant multimerization of the initial DNA molecule upon introduction to cells. Here, we describe an approach that efficiently forms single-copy HACs. It employs a ~750 kb construct that is sufficiently large to house the distinct chromatin types present at the inner and outer centromere, obviating the need to multimerize. Delivery to mammalian cells is streamlined by employing yeast spheroplast fusion. These developments permit faithful chromosome engineering in the context of metazoan cells.
PubMed: 37546784
DOI: 10.1101/2023.06.30.547284 -
Current Hematologic Malignancy Reports Jun 2024Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the... (Review)
Review
PURPOSE OF REVIEW
Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice.
RECENT FINDINGS
New molecular technologies have allowed the detection of MRD to levels as low as 10. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.
PubMed: 38888822
DOI: 10.1007/s11899-024-00736-9