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Clinical Lymphoma, Myeloma & Leukemia May 2024The development of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) from a fatal... (Review)
Review
The development of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) from a fatal disease to an often-indolent illness that, when managed effectively, can restore a life expectancy close to that of the normal population. Bosutinib is a second-generation TKI approved for adults with Ph-positive CML in chronic phase, accelerated phase, or blast phase that is resistant or intolerant to prior therapy, and for newly diagnosed Ph-positive chronic phase CML. This review details the efficacy of bosutinib for the treatment of CML in the first- and second-line settings, as well as in third- and later-line settings for high-risk patients resistant or intolerant to at least 2 TKIs. It also outlines bosutinib studies that provide evidence for dose-optimization strategies that can be used to improve efficacy and effectively manage adverse events. The studies that provide evidence for specific patient populations benefiting particularly from bosutinib dose-optimization strategies are also discussed. The well-established, long-term side-effect profile and the potential to make dose adjustments with bosutinib make it an appropriate treatment option for patients with CML. Bosutinib has demonstrated a positive impact on health-related quality of life and an important role in the long-term treatment of patients with CML.
Topics: Humans; Aniline Compounds; Nitriles; Quinolines; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Antineoplastic Agents; Treatment Outcome
PubMed: 38278737
DOI: 10.1016/j.clml.2024.01.005 -
Journal of Cancer Research and... Jan 2024Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm that is genetically characterized by the presence of the Philadelphia (Ph) chromosome. Variant Ph...
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm that is genetically characterized by the presence of the Philadelphia (Ph) chromosome. Variant Ph translocation has been observed in 5% to 10% of the CML cases. In the previous studies, many different types of variant Ph translocations have been observed involving chromosomes 1p36, 3p21, 5q13, 6p21, 9q22, 11q13, 12p13, 17p13, and 10p15. According to the published literature, only two cases with the complex translocations involving long arm of chromosome 16 at band q24 have been reported. We report two female patients with complex translocation (three-way) involving chromosomes 9, 22, and 16 at breakpoint q24 and both patients responded well to Imatinib. The present study included 469 patients of clinically diagnosed CML patients who were referred for cytogenetic analysis to our laboratory. Cytogenetic analysis was performed by GTG banding, and the karyotype was designated according to the International System for Human Cytogenetic Nomenclature. Fluorescence in situ hybridization (FISH) analysis was performed for complex and variant BCR-ABL cases. Of total 469 cases, 248 patients showed classical Ph chromosome [t(9;22)(q34;q11.2)], 198 cases were normal, and 23 patients had variant and complex Ph chromosome translocation. Two patients showed three-way translocation involving long arm of chromosomes 9, 22, and 16 at band 9q34, 22q11.2, and 16q24. In this report, patients with variant Ph translocation did not have a significantly different outcome as compared to the classical translocation. Both cases responded well to Imatinib.
PubMed: 38261414
DOI: 10.4103/jcrt.jcrt_274_21 -
BioRxiv : the Preprint Server For... Jan 2024Lyme disease is a tick-borne infection caused by the spirochete () . species have highly fragmented genomes composed of a linear chromosome and a constellation of...
Lyme disease is a tick-borne infection caused by the spirochete () . 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 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 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 region and revealed that ϕBB-1 packages linear cp32s via a headful mechanism with preferentially packaging of plasmids containing the cp32 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 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.
PubMed: 38260690
DOI: 10.1101/2024.01.08.574763 -
Journal of Clinical Immunology Jan 2024
PubMed: 38252398
DOI: 10.1007/s10875-024-01655-3 -
Medicine Jan 2024Imatinib is a standard treatment for Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML), but its efficacy in rare BCR::ABL variants is underexplored. (Review)
Review
RATIONALE
Imatinib is a standard treatment for Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML), but its efficacy in rare BCR::ABL variants is underexplored.
PATIENT CONCERNS
A 67-year-old woman was admitted to the Second Affiliated Hospital of Xi'an Jiaotong University in March 2022 due to elevated white blood cells.
DIAGNOSIS
Karyotype analysis revealed clonal abnormalities involving the variant t(9;22) and positive results for atypical BCR::ABL variants (e14a3 and e13a3). The clinical diagnosis was CML, chronic phase, Ph+, with rare BCR::ABL-e13a3- and BCR::ABL-e14a3-positive findings.
INTERVENTION
The patient was administered daily imatinib mesylate (400 mg).
OUTCOMES
After 4 weeks, a swift molecular response was observed: BCR::ABL-e13a3 transcript level at 2.82 × 10-1 (28.24%), and BCR::ABL-e14a3 transcript level at 4.68 × 10-1 (46.76%). Within 3 months, a complete cytogenetic response was achieved, with a Ph chromosome ratio of 0. Early molecular response was evident as BCR::ABL-e13a3 transcript level reached 5.11 × 10-3 (0.51%), and BCR::ABL-e14a3 transcript level at 6.26 × 10-3 (0.63%). The imatinib mesylate treatment continued without significant toxicity.
LESSONS
This case emphasizes the potential effectiveness of imatinib mesylate in managing rare BCR::ABL fusion gene variants of CML. Screening for these atypical variants is advised for suspected CML patients who test negative for common BCR::ABL fusion gene variants. The presented case underscores the positive outcomes achieved with imatinib treatment for a patient with rare BCR::ABL variants, contributing valuable insights for the management of similar cases. Screening for unusual fusion gene variants should be a consideration in CML diagnosis for comprehensive treatment strategies.
Topics: Female; Humans; Aged; Imatinib Mesylate; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome; Karyotyping
PubMed: 38241589
DOI: 10.1097/MD.0000000000036728 -
Haematologica Jan 2024Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute...
Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.
PubMed: 38235508
DOI: 10.3324/haematol.2023.284228 -
BioRxiv : the Preprint Server For... Dec 2023DNA 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 both bovine and mouse cleavage stage embryos progress through S-phase in a defined pattern. Late replicating regions are associated with the nuclear lamina from the first cell cycle after fertilization, and contain few active origins, and few but long genes. 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 segregation of soma and germ line. Our studies show that the formation of early and late replicating regions is among the first layers of epigenetic regulation established on the mammalian genome after fertilization.
PubMed: 38234839
DOI: 10.1101/2023.12.25.573304 -
Cureus Dec 2023Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase...
Introduction The overall survival (OS) of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has improved with the combination of tyrosine kinase inhibitor (TKI) with intensive chemotherapy. In recent years, there has been increased interest in the possibility of long-term survival without allogeneic hematopoietic stem cell transplantation (HSCT) or maintenance therapy. The aim of this study was to determine the effectiveness of treatment and the resultant outcomes in Ph+ALL patients using real-world data. Methods We performed a single-center retrospective analysis utilizing Akita University Hospital data (Akita, Japan) from November 2000 to June 2023 to evaluate the outcomes of TKI with intensive chemotherapy for Ph+ALL. Results Twenty-three patients with Ph+ALL were treated with intensive chemotherapy combined with TKI, including six imatinib, four dasatinib, and 13 ponatinib. The median patient age was 53 years (range; 28-67). Eighteen patients (78%) achieved complete molecular remission (CMR) within three months. HSCT was performed in 16 patients (70%), all of whom did not receive post-transplant TKI maintenance therapy. Six of the seven patients who did not undergo HSCT received maintenance therapy with ponatinib after intensive chemotherapy. The three-year OS was 81%. Ponatinib treatment resulted in a much higher OS rate than imatinib/dasatinib (100% vs. 60%; =0.011). CMR within three months was identified as a prognostic factor for molecular relapse-free survival (hazard ratio (HR)=0.22; =0.027). CD20 positivity was identified as a risk factor for hematological relapse (HR=5.2, =0.032). Conclusion Even in a single-center cohort study, ponatinib, as a combination TKI with intensive chemotherapy or maintenance therapy, may improve the prognosis of Ph+ALL. Patients with CMR within three months might not necessarily need to receive HSCT, but a subsequent treatment-free status could have been achieved only by HSCT. Furthermore, CD20 positivity may be a useful biomarker for future treatment decisions in patients with Ph+ALL.
PubMed: 38222242
DOI: 10.7759/cureus.50416 -
Cell Death & Disease Jan 2024Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic...
Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic strategy against cancer. One transmembrane component of the NPC is POM121, encoded by a tandem gene locus POM121A/C on chromosome 7. Overexpression of POM121 is associated with metabolic diseases (e.g., diabetes) and unfavorable clinical outcome in patients with colorectal cancer (CRC). Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor with anti-diabetic and anti-tumoral efficacy. It is inhibited by export from the nucleus to the cytosol via the RAS-RAF-MEK1/2-ERK1/2 signaling pathway, a major oncogenic driver of CRC. We therefore hypothesized that POM121 participates in the transport of PPARγ across the NPC to regulate its transcriptional activity on genes involved in metabolic and tumor control. We found that POM121A/C mRNA was enriched and POM121 protein co-expressed with PPARγ in tissues from CRC patients conferring poor prognosis. Its interactome was predicted to include proteins responsible for tumor metabolism and immunity, and in-silico modeling provided insights into potential 3D structures of POM121. A peptide region downstream of the nuclear localization sequence (NLS) of POM121 was identified as a cytoplasmic interactor of PPARγ. POM121 positivity correlated with the cytoplasmic localization of PPARγ in patients with KRAS mutant CRC. In contrast, POM121A/C silencing by CRISPR/Cas9 sgRNA or siRNA enforced nuclear accumulation of PPARγ and activated PPARγ target genes promoting lipid metabolism and cell cycle arrest resulting in reduced proliferation of human CRC cells. Our data suggest the POM121-PPARγ axis as a potential drugable target in CRC.
Topics: Humans; Nuclear Pore; PPAR gamma; RNA, Guide, CRISPR-Cas Systems; Nuclear Pore Complex Proteins; Transcription Factors; Neoplasms; Membrane Glycoproteins
PubMed: 38177114
DOI: 10.1038/s41419-023-06371-1 -
Cancer Diagnosis & Prognosis 2024Acute lymphoblastic leukemia (ALL) is a blood malignancy characterized by a rapid proliferation of lymphoid progenitor cells. Extramedullary relapse (EMR) is the...
BACKGROUND/AIM
Acute lymphoblastic leukemia (ALL) is a blood malignancy characterized by a rapid proliferation of lymphoid progenitor cells. Extramedullary relapse (EMR) is the recurrence of leukemia that occurs outside the bone marrow. The central nervous system is the most prevalent site of EMR in ALL, whereas other organs, particularly the renal organs, are less commonly involved.
CASE REPORT
A 49-year-old man diagnosed with Philadelphia chromosome-negative ALL (Ph-negative ALL) received a second umbilical cord blood transplant (uCBT) and was confirmed to be in his third hematological complete remission. However, the perirenal mass lesion emerged after two weeks, and was difficult to detect on echography in the prone position. We successfully performed a percutaneous biopsy of the mass in a sitting position and pathologically identified it as EMR. After the diagnosis, chemotherapy was restarted, and the patient was scheduled to receive a third uCBT.
CONCLUSION
This is the first report of EMR in a perirenal lesion of ALL and shows that this novel biopsy can be performed as a renal biopsy, even in a sitting position. This case is the first to describe a biopsy technique in detail and demonstrates the value of collaboration between hematologists and nephrologists in diagnosing EMR of the kidneys.
PubMed: 38173667
DOI: 10.21873/cdp.10287