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G3 (Bethesda, Md.) Jun 2024In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases....
In humans, the prevalence of congenital microphthalmia is estimated to be 0.2-3.0 for every 10,000 individuals, with nonocular involvement reported in ∼80% of cases. Inherited eye diseases have been widely and descriptively characterized in dogs, and canine models of ocular diseases have played an essential role in unraveling the pathophysiology and development of new therapies. A naturally occurring canine model of a syndromic disorder characterized by microphthalmia was discovered in the Portuguese water dog. As nonocular findings included tooth enamel malformations, stunted growth, anemia, and thrombocytopenia, we hence termed this disorder Canine Congenital Microphthalmos with Hematopoietic Defects. Genome-wide association study and homozygosity mapping detected a 2 Mb candidate region on canine chromosome 4. Whole-genome sequencing and mapping against the Canfam4 reference revealed a Short interspersed element insertion in exon 2 of the DNAJC1 gene (g.74,274,883ins[T70]TGCTGCTTGGATT). Subsequent real-time PCR-based mass genotyping of a larger Portuguese water dog population found that the homozygous mutant genotype was perfectly associated with the Canine Congenital Microphthalmos with Hematopoietic Defects phenotype. Biallelic variants in DNAJC21 are mostly found to be associated with bone marrow failure syndrome type 3, with a phenotype that has a certain degree of overlap with Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and reports of individuals showing thrombocytopenia, microdontia, and microphthalmia. We, therefore, propose Canine Congenital Microphthalmos with Hematopoietic Defects as a naturally occurring model for DNAJC21-associated syndromes.
Topics: Animals; Dogs; Microphthalmos; Disease Models, Animal; Genome-Wide Association Study; Phenotype; Genotype; Homozygote; Dog Diseases; Syndrome; Female; Male
PubMed: 38682429
DOI: 10.1093/g3journal/jkae067 -
BMC Cancer Apr 2024In low-income countries there is insufficient evidence on hematological, clinical, cytogenetic and molecular profiles among new CML patients. Therefore, we performed...
Hematological, clinical, cytogenetic and molecular profiles of confirmed chronic myeloid leukemia patients at presentation at a tertiary care teaching hospital in Addis Ababa, Ethiopia: a cross-sectional study.
BACKGROUND
In low-income countries there is insufficient evidence on hematological, clinical, cytogenetic and molecular profiles among new CML patients. Therefore, we performed this study among newly confirmed CML patients at Tikur Anbesa Specialized Hospital (TASH), Ethiopia.
OBJECTIVE
To determine the hematological, clinical, cytogenetic and molecular profiles of confirmed CML patients at tertiary care teaching hospital in Addis Ababa, Ethiopia.
METHODS
A facility-based cross-sectional study was conducted to evaluate hematological, clinical, cytogenetic and molecular profiles of confirmed CML patients at TASH from August 2021 to December 2022. A structured questionnaire was used to collect the patients' sociodemographic information, medical history and physical examination, and blood samples were also collected for hematological, cytogenetic and molecular tests. Descriptive statistics were used to analyze the sociodemographic, hematological, clinical, cytogenetic and molecular profiles of the study participants.
RESULTS
A total of 251 confirmed new CML patients were recruited for the study. The majority of patients were male (151 [60.2%]; chronic (CP) CML, 213 [84.7%]; and had a median age of 36 years. The median (IQR) WBC, RBC, HGB and PLT counts were 217.7 (155.62-307.4) x10/µL, 3.2 (2.72-3.6) x10/µL, 9.3 (8.2-11) g/dl and 324 (211-499) x 10/µL, respectively. All patients had leukocytosis, and 92.8%, 95.6% and 99.2% of the patients developed anemia, hyperleukocytosis and neutrophilia, respectively. Fatigue, abdominal pain, splenomegaly and weight loss were the common signs and symptoms observed among CML patients. Approximately 86.1% of the study participants were Philadelphia chromosome positive (Ph+) according to fluorescence in situ hybridization (FISH). P210, the major breakpoint protein, transcript was detected by both qualitative polymerase chain reaction (PCR) and quantitative real time polymerase chain reaction (PCR).
CONCLUSION
During presentation, most CML patients presented with hyperleukocytosis, neutrophilia and anemia at TASH, Addis Ababa. Fatigue, abdominal pain, splenomegaly and weight loss were the most common signs and symptoms observed in the CML patients. Most CML patients were diagnosed by FISH, and p120 was detected in all CML patients diagnosed by PCR. The majority of CML patients arrive at referral center with advanced signs and symptoms, so better to decentralize the service to peripheral health facilities.
Topics: Humans; Male; Cross-Sectional Studies; Female; Ethiopia; Adult; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hospitals, Teaching; Middle Aged; Young Adult; Adolescent; Tertiary Care Centers; Aged; Cytogenetic Analysis; Fusion Proteins, bcr-abl; Tertiary Healthcare
PubMed: 38664756
DOI: 10.1186/s12885-024-12282-x -
BioRxiv : the Preprint Server For... Apr 2024The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary fibrous tumors (SFTs) are neoplasms of...
The pathogenesis of many rare tumor types is poorly understood, preventing the design of effective treatments. Solitary fibrous tumors (SFTs) are neoplasms of mesenchymal origin that affect 1/1,000,000 individuals every year and are clinically assimilated to soft tissue sarcomas. SFTs can arise throughout the body and are usually managed surgically. However, 30-40% of SFTs will relapse local-regionally or metastasize. There are no systemic therapies with durable activity for malignant SFTs to date. The molecular hallmark of SFTs is a gene fusion between the and loci on chromosome 12, resulting in a chimeric protein of poorly characterized function called NAB2-STAT6. We use primary samples and an inducible cell model to discover that NAB2-STAT6 operates as a transcriptional coactivator for a specific set of enhancers and promoters that are normally targeted by the EGR1 transcription factor. In physiological conditions, NAB2 is primarily localized to the cytoplasm and only a small nuclear fraction is available to operate as a co-activator of EGR1 targets. NAB2-STAT6 redirects NAB1, NAB2, and additional EGR1 to the nucleus and bolster the expression of neuronal EGR1 targets. The STAT6 moiety of the fusion protein is a major driver of its nuclear localization and further contributes to NAB2's co-activating abilities. In primary tumors, NAB2-STAT6 activates a neuroendocrine gene signature that sets it apart from most sarcomas. These discoveries provide new insight into the pathogenesis of SFTs and reveal new targets with therapeutic potential.
PubMed: 38659891
DOI: 10.1101/2024.04.15.589533 -
Journal of Hematology & Oncology Apr 2024The chemo-free concept represents a new direction for managing adult patients with Ph-positive acute lymphoblastic leukemia (Ph + ALL). The tyrosine kinase... (Review)
Review
The chemo-free concept represents a new direction for managing adult patients with Ph-positive acute lymphoblastic leukemia (Ph + ALL). The tyrosine kinase inhibitors (TKIs), blinatumomab and venetoclax serve as the backbone of chemo-free regimens; several prospective studies involving these drugs have demonstrated high remission rates and promising, albeit short, survival outcomes. This review summarizes the latest updates on chemo-free regimens in the treatment of adult patients with Ph + ALL, presented at the 2023 ASH annual meeting.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Protein Kinase Inhibitors; Congresses as Topic
PubMed: 38627786
DOI: 10.1186/s13045-024-01539-4 -
International Journal of Molecular... Apr 2024The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera...
Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.
The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.
Topics: Humans; Comparative Genomic Hybridization; Thrombocythemia, Essential; Polymorphism, Single Nucleotide; Primary Myelofibrosis; Retrospective Studies; Cytogenetic Analysis; Disease Progression
PubMed: 38612873
DOI: 10.3390/ijms25074061 -
Frontiers in Cell and Developmental... 2024Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is... (Review)
Review
Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 (), calreticulin (), or thrombopoietin receptor/myeloproliferative leukemia (). mutations have been described essentially in and wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting and mutations have been found in Ph-negative MPNs. translocation and mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of translocation with a coexisting mutation is even more uncommon. Herein, starting from a routinely diagnosed case of -mutated primary myelofibrosis subsequently acquiring translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with and co-occurrence.
PubMed: 38596359
DOI: 10.3389/fcell.2024.1391078 -
Frontiers in Oncology 2024Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) exhibit phenotypic similarities with JAK/STAT-unmutated idiopathic erythrocytosis and thrombocytosis...
TNF-α is a predictive marker in distinguishing myeloproliferative neoplasm and idiopathic erythrocytosis/thrombocytosis: development and validation of a non-invasive diagnostic model.
PURPOSE
Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) exhibit phenotypic similarities with JAK/STAT-unmutated idiopathic erythrocytosis and thrombocytosis (IE/IT). We aimed to develop a clinical diagnostic model to discern MPN and IE/IT.
METHODS
A retrospective study was performed on 77 MPN patients and 32 IE/IT patients in our center from January 2018 to December 2023. We investigated the role of hemogram, cytokine and spleen size in differentiating MPN and IE/IT among newly onset erythrocytosis and thrombocytosis patients. Independent influencing factors were integrated into a nomogram for individualized risk prediction. The calibration and discrimination ability of the model were evaluated by concordance index (C-index), calibration curve.
RESULTS
MPN had significantly higher TNF-α level than IE/IT, and the TNF-α level is correlated with MF-grade. Multivariable analyses revealed that TNF-α, PLT count, age, size of spleen were independent diagnostic factors in differentiating MPN and IE/IT. Nomograms integrated the above 4 factors for differentiating MPN and IE/IT was internally validated and had good performance, the C-index of the model is 0.979.
CONCLUSION
The elevation of serum TNF-α in MPN patients is of diagnostic significance and is correlated with the severity of myelofibrosis. The nomogram incorporating TNF-α with age, PLT count and spleen size presents a noteworthy tool in the preliminary discrimination of MPN patients and those with idiopathic erythrocytosis or thrombocytosis. This highlights the potential of cytokines as biomarkers in hematologic disorders.
PubMed: 38585007
DOI: 10.3389/fonc.2024.1369346 -
Cancer Reports (Hoboken, N.J.) Apr 2024Adhesion of cancer cells to extracellular matrix laminin through the integrin superfamily reportedly induces drug resistance. Heterodimers of integrin α6 (CD49f) with...
BACKGROUND
Adhesion of cancer cells to extracellular matrix laminin through the integrin superfamily reportedly induces drug resistance. Heterodimers of integrin α6 (CD49f) with integrin β1 (CD29) or β4 (CD104) are major functional receptors for laminin. Higher CD49f expression is reportedly associated with a poorer response to induction therapy in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Moreover, a xenograft mouse model transplanted with primary BCP-ALL cells revealed that neutralized antibody against CD49f improved survival after chemotherapy.
AIMS
Considering the poor outcomes in Philadelphia chromosome (Ph)-positive ALL treated with conventional chemotherapy without tyrosine kinase inhibitors, we sought to investigate an involvement of the laminin adhesion.
METHODS AND RESULTS
Ph-positive ALL cell lines expressed the highest levels of CD49f among the BCP-ALL cell lines with representative translocations, while CD29 and CD104 were ubiquitously expressed in BCP-ALL cell lines. The association of Ph-positive ALL with high levels of CD49f gene expression was also confirmed in two databases of childhood ALL cohorts. Ph-positive ALL cell lines attached to laminin and their laminin-binding properties were disrupted by blocking antibodies against CD49f and CD29 but not CD104. The cell surface expression of CD49f, but not CD29 and CD104, was downregulated by imatinib treatment in Ph-positive ALL cell lines, but not in their T315I-acquired sublines. Consistently, the laminin-binding properties were disrupted by the imatinib pre-treatment in the Ph-positive ALL cell line, but not in its T315I-acquired subline.
CONCLUSION
BCR::ABL1 plays an essential role in the laminin adhesion of Ph-positive ALL cells through upregulation of CD49f.
Topics: Animals; Humans; Mice; Imatinib Mesylate; Integrin alpha6; Laminin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Up-Regulation
PubMed: 38577721
DOI: 10.1002/cnr2.2034