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Clinical Case Reports Feb 2024We report a case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome-positive acute B-lymphoblastic leukemia. The annular appearance...
We report a case of leukemia cutis showing annular erythema during the course of Philadelphia chromosome-positive acute B-lymphoblastic leukemia. The annular appearance may be developed by immunomodulatory effects of blinatumomab.
PubMed: 38344344
DOI: 10.1002/ccr3.8474 -
Diagnostics (Basel, Switzerland) Jan 2024Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome resulting from the translocation of t(9;22)(q34;q11), producing the :: fusion gene....
Chronic myeloid leukemia (CML) is characterized by the Philadelphia (Ph) chromosome resulting from the translocation of t(9;22)(q34;q11), producing the :: fusion gene. Variant Ph chromosome translocations, involving rearrangements in chromosomes other than 9 and 22, occur in 5-10% of CML cases. Herein, we report a unique case of a 36-year-old male with a four-way variant Ph chromosome. Conventional chromosomal analysis performed on bone marrow aspirate samples showed 46, XY, t(1;9;22;16)(q21;q34;q11.2;q24). Nested RT-PCR of the :: gene revealed a major :: rearrangement. The treatment with nilotinib achieved a complete hematologic, cytogenetic, and molecular response after 12 months.
PubMed: 38337818
DOI: 10.3390/diagnostics14030303 -
Indian Journal of Ophthalmology May 2024The BRCA-associated protein1 (BAP1) immunohistochemical (IHC) stain has emerged as a powerful and inexpensive prognostic tool in uveal melanoma (UM), correlating with UM...
PURPOSE
The BRCA-associated protein1 (BAP1) immunohistochemical (IHC) stain has emerged as a powerful and inexpensive prognostic tool in uveal melanoma (UM), correlating with UM genetics and outcome. The data on the reliability of BAP1 immunohistochemistry in previously irradiated UM is scant. We aim to assess BAP1 IHC in post-Iodine-125 plaque brachytherapy-treated UM-enucleated eyes.
METHODS
In a case-control study, the medical records of all patients who underwent enucleation for UM at a major Ocular Oncology Service from December 1 st , 2007 to December 31 st , 2014 were reviewed. All cases with either chromosome 3 (ch3) status or sufficient follow-up (>5 years or metastasis) were selected. Nuclear BAP1 (nBAP1) immunoreactivity was interpreted as intact (positive in >90% of nuclei), lost (positive in <5% of nuclei), or heterogeneous (positive in 5-90% of nuclei). Retina and intratumoral blood vessels served as internal positive controls.
RESULTS
A comparison of 34 postbrachytherapy UM secondary-enucleated eyes with 47 nonbrachytherapy primary enucleated controls revealed no significant difference with respect to nBAP1 IHC (lost in 41% vs 51%, P = 0.19), ch3 status (ch3 monosomy in 59% vs 60%, P = 0.48), and outcome (metastatic disease in 44% vs 47%, P = 0.8). Association of nBAP1 IHC with ch3 status and outcome [intact nBAP1/(ch3 disomy and/or no metastasis) and lost nBAP1 (ch3 monosomy and/or metastasis)] in post-brachytherapy UM was significantly lower when compared with non-brachytherapy tumors [21/30 (70%) vs 41/44 (93%), P = 0.004*].
CONCLUSION
Although nBAP1 IHC stain is a strong prognostic tool in UM, its association with ch3 status, and outcome in postbrachytherapy UM was significantly lower compared with nonbrachytherapy tumors due to pitfalls in the interpretation of nBAP1 immunoreactivity in irradiated UM. This test should be used judiciously in the prognostication of postbrachytherapy-enucleated UM.
PubMed: 38324631
DOI: 10.4103/IJO.IJO_648_23 -
Journal of Cellular and Molecular... Feb 2024Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in...
Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).
Topics: Animals; Humans; Mice; Carcinogenesis; Cell Transformation, Neoplastic; Imatinib Mesylate; Protein Kinase Inhibitors; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; STAT5 Transcription Factor; Telomeric Repeat Binding Protein 2; Oncogene Proteins, Fusion; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38323741
DOI: 10.1111/jcmm.18114 -
Annals of Hematology May 2024Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome and the consequent BCR::ABL1 oncoprotein. In the...
Late relapse of chronic myeloid leukemia after allogeneic bone marrow transplantation points to KANSARL (KANSL1::ARL17A) alteration: a case report with insights on the molecular landscape.
Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome and the consequent BCR::ABL1 oncoprotein. In the era before the introduction of tyrosine kinase inhibitors (TKIs), the only potentially curative treatment was allogeneic hematopoietic stem cell transplantation (HSCT). Here, we present the case of a patient affected by CML who experienced a relapse 20 years after allogeneic HSCT. Following relapse, the patient was treated with imatinib and bosutinib, resulting in a deep molecular response and successfully discontinued treatment. Additional analysis including whole-exome sequencing and RNA sequencing provided some insights on the molecular mechanisms of the relapse: the identification of the fusion transcript KANSL1::ARL17A (KANSARL), a cancer predisposition fusion gene, could justify a condition of genomic instability which may be associated with the onset and/or probably the late relapse of his CML.
Topics: Humans; Bone Marrow Transplantation; Fusion Proteins, bcr-abl; Hematopoietic Stem Cell Transplantation; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Recurrence; Oncogene Proteins, Fusion
PubMed: 38321229
DOI: 10.1007/s00277-024-05649-4 -
Nature Communications Feb 2024Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here...
Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.
Topics: Animals; Mice; Humans; Bone Marrow; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Philadelphia Chromosome; Macrophages; Fusion Proteins, bcr-abl; Tumor Microenvironment
PubMed: 38316788
DOI: 10.1038/s41467-024-45471-0 -
MicroPublication Biology 2024Cellular processes rely on proteins with temperature-dependent stability and activity. While thermosensitivity in biological networks is well-explored, the effect of...
Cellular processes rely on proteins with temperature-dependent stability and activity. While thermosensitivity in biological networks is well-explored, the effect of temperature on complex mechanochemical assemblies, like the spindle, is rarely studied. We examined fission yeast spindle dynamics and chromosome segregation from 15⁰C to 40⁰C. Our findings reveal that these parameters follow U-shaped temperature-dependent curves but reach their minima at different temperatures. Specifically, spindle dynamics peak around 35⁰C, whereas chromosome segregation defects are minimized at 25⁰C. This suggests a scenario in which mitotic errors are tolerated to expedite rapid cell cycle progression.
PubMed: 38287927
DOI: 10.17912/micropub.biology.001048 -
Genome Biology Jan 2024Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY is present in...
BACKGROUND
Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY is present in the kidney and increases with age and chronic kidney disease.
RESULTS
The likelihood of a cell having LOY varies depending on its location in the nephron. Cortical epithelial cell types have a greater proportion of LOY than medullary or glomerular cell types, which may reflect their proliferative history. Proximal tubule cells are the most abundant cell type in the cortex and are susceptible to hypoxic injury. A subset of these cells acquires a pro-inflammatory transcription and chromatin accessibility profile associated with expression of HAVCR1, VCAM1, and PROM1. These injured epithelial cells have the greatest proportion of LOY and their presence predicts future kidney function decline. Moreover, proximal tubule cells with LOY are more likely to harbor additional large chromosomal gains and express pro-survival pathways. Spatial transcriptomics localizes injured proximal tubule cells to a pro-fibrotic microenvironment where they adopt a secretory phenotype and likely communicate with infiltrating immune cells.
CONCLUSIONS
We hypothesize that LOY is an indicator of increased DNA damage and potential marker of cellular senescence that can be applied to single-cell datasets in other tissues.
Topics: Humans; Male; Chromosomes, Human, Y; Mosaicism; Aging; Phenotype; Renal Insufficiency, Chronic
PubMed: 38287344
DOI: 10.1186/s13059-024-03173-2 -
Frontiers in Oncology 2023Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is the... (Review)
Review
Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is the key genetic event of CML, whereas mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of and has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, translocation occurs in patients with a history of -positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of and co-occurrence. The interaction between and clones during the disease course as well as therapy and outcome are presented.
PubMed: 38282677
DOI: 10.3389/fonc.2023.1329298 -
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