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Stem Cell Reviews and Reports Jun 2024Additional sex combs-like 1 (ASXL1) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for...
Additional sex combs-like 1 (ASXL1) is an epigenetic modulator frequently mutated in myeloid malignancies, generally associated with poor prognosis. Current models for ASXL1-mutated diseases are mainly based on the complete deletion of Asxl1 or overexpression of C-terminal truncations in mice models. However, these models cannot fully recapitulate the pathogenesis of myeloid malignancies. Patient-derived induced pluripotent stem cells (iPSCs) provide valuable disease models that allow us to understand disease-related molecular pathways and develop novel targeted therapies. Here, we generated iPSCs from a patient with myeloproliferative neoplasm carrying a heterozygous ASXL1 mutation. The iPSCs we generated exhibited the morphology of pluripotent cells, highly expressed pluripotent markers, excellent differentiation potency in vivo, and normal karyotype. Subsequently, iPSCs with or without ASXL1 mutation were induced to differentiate into hematopoietic stem/progenitor cells, and we found that ASXL1 mutation led to myeloid-biased output and impaired erythroid differentiation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that terms related to embryonic development, myeloid differentiation, and immune- and neural-related processes were most enriched in the differentially expressed genes. Western blot demonstrated that the global level of H2AK119ub was significantly decreased when mutant ASXL1 was present. Chromatin Immunoprecipitation Sequencing showed that most genes associated with stem cell maintenance were upregulated, whereas occupancies of H2AK119ub around these genes were significantly decreased. Thus, the iPSC model carrying ASXL1 mutation could serve as a potential tool to study the pathogenesis of myeloid malignancies and to screen targeted therapy for patients.
PubMed: 38884929
DOI: 10.1007/s12015-024-10737-z -
Harefuah Jun 2024Imatinib is a tyrosine kinase inhibitor and is used for the treatment of chronic myeloid leukemia (CML) since 2002. We present a patient who suffered from fluid...
Imatinib is a tyrosine kinase inhibitor and is used for the treatment of chronic myeloid leukemia (CML) since 2002. We present a patient who suffered from fluid retention and periorbital edema secondary to this drug.
Topics: Humans; Imatinib Mesylate; Edema; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Antineoplastic Agents; Male; Middle Aged; Female
PubMed: 38884296
DOI: No ID Found -
Biochemia Medica Jun 2024This case report describes a case of pseudonormokalemia, true hypokalemia. Often, only laboratory values outside the normal range gain attention and false normal results...
This case report describes a case of pseudonormokalemia, true hypokalemia. Often, only laboratory values outside the normal range gain attention and false normal results are at risk of not being noticed. However, a disease state may be masked by another pathological process. Here, a 50-year old male was admitted to the Department of Internal Medicine due to sepsis from a dental infection. Initially, serum potassium measurement revealed a normal value of 4 mmol/L (reference interval 3.8-5.1 mmol/L). Thrombocyte number was above 500x10/L. Due to our policy to recommend a repeated measurement of potassium in whole blood or heparin plasma if a patient has thrombocytosis, pseudonormokalemia was identified because the heparin plasma potassium value was only 2.9 mmol/L (reference interval 3.5-4.8 mmol/L). The physiological difference between serum and plasma concentration is no more than 0.3 mmol/L. In this case, potassium concentration were falsely elevated in the serum sample, probably caused by the high number of platelets releasing potassium during clotting. Interpretative comments in patients with thrombocytosis over 500x10/L recommending plasma potassium measurement are helpful. The best way to eliminate pseudohyperkalemia and pseudonormokalemia phenomena caused by thrombocytosis is to completely change towards heparin plasma as the standard material.
Topics: Humans; Male; Potassium; Middle Aged; Hypokalemia; Thrombocytosis
PubMed: 38882587
DOI: 10.11613/BM.2024.021002 -
Human Pathology Jul 2024CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but...
CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.
Topics: Humans; Receptors, Colony-Stimulating Factor; Male; Mutation; Middle Aged; Female; Aged; Leukemia, Neutrophilic, Chronic; Retrospective Studies; Adult; Young Adult; Aged, 80 and over; Myeloproliferative Disorders; Leukemia, Myeloid, Acute; DNA Mutational Analysis; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Genetic Predisposition to Disease; Biomarkers, Tumor; Phenotype
PubMed: 38879086
DOI: 10.1016/j.humpath.2024.06.008 -
BMC Cancer Jun 2024The role of familial influence in chronic myeloid leukaemia (CML) occurrence is less defined. Previously, we conducted a study to determine the prevalence of harbouring...
BACKGROUND
The role of familial influence in chronic myeloid leukaemia (CML) occurrence is less defined. Previously, we conducted a study to determine the prevalence of harbouring BCR::ABL1 in our local adult normal population (designated as Study). We present our current study, which investigated the prevalence of harbouring BCR::ABL1 in the normal first-degree relatives of local CML patients (designated as Study). We compared and discussed the prevalence of Study and Study to assess the familial influence in CML occurrence.
METHODS
Study was a cross-sectional study using convenience sampling, recruiting first-degree relatives of local CML patients aged ≥ 18 years old without a history of haematological tumour. Real-time quantitative polymerase chain reaction standardised at the International Scale (BCR::ABL1-qPCR) was performed according to standard laboratory practice and the manufacturer's protocol.
RESULTS
A total of 96 first-degree relatives from 41 families, with a mean age of 39 and a male-to-female ratio of 0.88, were enrolled and analysed. The median number of relatives per family was 2 (range 1 to 5). Among them, 18 (19%) were parents, 39 (41%) were siblings, and 39 (41%) were offspring of the CML patients. Study revealed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives was 4% (4/96), which was higher than the prevalence in the local normal population from Study, 0.5% (1/190). All four positive relatives were Chinese, with three of them being female (p > 0.05). Their mean age was 39, compared to 45 in Study. The BCR::ABL1-qPCR levels ranged between 0.0017% and 0.0071%, similar to Study (0.0023% to 0.0032%) and another study (0.006% to 0.016%).
CONCLUSION
Our study showed that the prevalence of harbouring BCR::ABL1 in the first-degree relatives of known CML patients was higher than the prevalence observed in the normal population. This suggests that familial influence in CML occurrence might exist but could be surpassed by other more dominant influences, such as genetic dilutional effects and protective genetic factors. The gender and ethnic association were inconsistent with CML epidemiology, suggestive of a higher familial influence in female and Chinese. Further investigation into this topic is warranted, ideally through larger studies with longer follow-up periods.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Female; Adult; Middle Aged; Cross-Sectional Studies; Prevalence; Fusion Proteins, bcr-abl; Family; Young Adult; Aged; Adolescent
PubMed: 38877512
DOI: 10.1186/s12885-024-12102-2 -
Virchows Archiv : An International... Jun 2024Herein is reported a series of five patients with myeloid neoplasms presenting hepatic complications in whose liver biopsy revealed obstruction of sinusoids by platelet...
Herein is reported a series of five patients with myeloid neoplasms presenting hepatic complications in whose liver biopsy revealed obstruction of sinusoids by platelet aggregates associated to liver extramedullary haematopoiesis. Indication of liver biopsies was jaundice, unexplained hepatomegaly or portal hypertension. Haematological disorders were classified according to the World Health Organisation. Molecular profile was established in all cases as well as grade of liver extramedullary haematopoiesis and myelofibrosis. The patients were four men and one woman aged from 50 to 82 years. Two patients had myeloproliferative neoplasm (triple negative primary myelofibrosis and JAK2-mutated essential thrombocytopenia), two patients had unclassifiable myelodysplastic/myeloproliferative neoplasm and one patient had chronic myelomonocytic leukaemia type 1. Liver biopsies revealed platelet aggregates occluding sinusoids in association with extramedullary haematopoiesis grade 1 in one patient, grade 2 in two patients and grade 3 in two patients. Two of these patients presented co-existing liver fibrosis due to chronic alcoholic consumption and ischemic heart failure. These five patients died from 2 to 23 months after liver biopsy due to acute myeloblastic leukaemia (three patients), portal hypertension (one patient) or other causes (acute heart failure). Intrahepatic sinusoidal microthromboses through platelet aggregates might cause portal hypertension or liver deficiency in patients with myeloid neoplasms, independently of JAK2 mutational status and grade of extramedullary haematopoiesis.
PubMed: 38877359
DOI: 10.1007/s00428-024-03844-2 -
Medicine Jun 2024This study aimed to assess hematological diseases next-generation sequencing (NGS) panel enhances the diagnosis and classification of myeloid neoplasms (MN) using the... (Observational Study)
Observational Study
This study aimed to assess hematological diseases next-generation sequencing (NGS) panel enhances the diagnosis and classification of myeloid neoplasms (MN) using the 5th edition of the WHO Classification of Hematolymphoid Tumors (WHO-HAEM5) and the International Consensus Classification (ICC) of Myeloid Tumors. A cohort of 112 patients diagnosed with MN according to the revised fourth edition of the WHO classification (WHO-HAEM4R) underwent testing with a 141-gene NGS panel for hematological diseases. Ancillary studies were also conducted, including bone marrow cytomorphology and routine cytogenetics. The cases were then reclassified according to WHO-HAEM5 and ICC to assess the practical impact of these 2 classifications. The mutation detection rates were 93% for acute myeloid leukemia (AML), 89% for myelodysplastic syndrome (MDS), 94% for myeloproliferative neoplasm (MPN), and 100% for myelodysplasia/myeloproliferative neoplasm (MDS/MPN) (WHO-HAEM4R). NGS provided subclassified information for 26 and 29 patients with WHO-HAEM5 and ICC, respectively. In MPN, NGS confirmed diagnoses in 16 cases by detecting JAK2, MPL, or CALR mutations, whereas 13 "triple-negative" MPN cases revealed at least 1 mutation. NGS panel testing for hematological diseases improves the diagnosis and classification of MN. When diagnosed with ICC, NGS produces more classification subtype information than WHO-HAEM5.
Topics: Humans; High-Throughput Nucleotide Sequencing; Female; Male; Middle Aged; Aged; Myeloproliferative Disorders; Adult; Myelodysplastic Syndromes; Mutation; Aged, 80 and over; Janus Kinase 2; World Health Organization; Leukemia, Myeloid, Acute; Receptors, Thrombopoietin; Calreticulin; Young Adult
PubMed: 38875377
DOI: 10.1097/MD.0000000000038556 -
Leukemia & Lymphoma Jun 2024There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to... (Review)
Review
There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of -mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.
PubMed: 38871488
DOI: 10.1080/10428194.2024.2361836 -
Blood Jun 2024
Topics: Humans; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Animals; Hematopoietic Stem Cells; Mice; Myeloproliferative Disorders; Interferons
PubMed: 38869916
DOI: 10.1182/blood.2024024448 -
Clinical Laboratory Jun 2024Polycythemia is a common medical problem, frequently acquired and reactive to secondary conditions. High-altitude-associated hypoxia contributes to the greater...
BACKGROUND
Polycythemia is a common medical problem, frequently acquired and reactive to secondary conditions. High-altitude-associated hypoxia contributes to the greater prevalence of polycythemia at altitude. Primary clonal polycythemia vera (PV), even though it is rare, requires a different therapeutic approach. Suspicion of PV usually drives the diagnostic workup of polycythemia.
METHODS
In this retrospective lab record study, we collected all JAK2 tests requested over a three-year period. We analyzed requests that were made for the evaluation of polycythemia. Complete blood count (CBC) and imaging of the abdomen were collected.
RESULTS
Out of 208 total requests, 136 were for the purpose of polycythemia evaluation. JAK2 mutation was positive (confirming the presence of PV) in 22 (16.7%) cases. PV patients have the usual demographics reported elsewhere. Additionally, PV patients exhibit distinct hemogram results featuring leukocytosis, thrombocytosis, and hypochromic microcytic red blood cells (RBCs) related to the associated iron deficiency.
CONCLUSIONS
Many patients with polycythemia at altitude might be unnecessarily considered for an evaluation of PV, if hemoglobin/hematocrit is the sole deciding criterion. PV patients have a distinct CBC pattern that can be exploited to better select patients with polycythemia for further evaluation and thus reduce unnecessary workups.
Topics: Humans; Polycythemia Vera; Retrospective Studies; Altitude; Female; Male; Middle Aged; Janus Kinase 2; Adult; Blood Cell Count; Aged; Mutation; Polycythemia
PubMed: 38868887
DOI: 10.7754/Clin.Lab.2023.231150