Numerous pathogenic exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; ) and type 2 (5bp insertion; ) being the most prevalent. Despite the universal pathobiology of MPN driven by various mutants, it is unclear why different mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in but not in MPN-model cells. The expression of could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting promoter region in cells as compared to cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in cells. Clinical validation showed significantly enhanced expression in -mutated MPN patients compared to -mutated cases, and thrombocytosis was less prominent in those with upregulation. This study provides indispensable insights into how different mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.
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http://dx.doi.org/10.3390/ijms24108747 | DOI Listing |
Blood Adv
January 2025
Oregon Health & Science University, Portland, Oregon, United States.
Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). CNL is a myeloproliferative neoplasm (MPN) driven by activating mutations in the Colony Stimulating Factor 3 Receptor (CSF3R), which cause excessive neutrophil production. Despite the high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia remains poorly understood.
View Article and Find Full Text PDFCurr Hematol Malig Rep
January 2025
Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Purpose Of Review: More than a decade following the discovery of Calreticulin (CALR) mutations as drivers of myeloproliferative neoplasms (MPN), advances in the understanding of CALR-mutant MPN continue to emerge. Here, we summarize recent advances in mehanistic understanding and in targeted therapies for CALR-mutant MPN.
Recent Findings: Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface.
Cureus
December 2024
Academic Affairs and Research, Orlando Regional Medical Center, Orlando, USA.
Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm (MPN) disorder characterized by persistent thrombocytosis and characterized by frequent association with cellular genetic alterations. The 10%-15% of ET that is not associated with genetic abnormalities is known as triple-negative essential thrombocythemia (TNET). A common complication observed in around 20% of ET patients is the development of acquired von Willebrand disease (AvWD).
View Article and Find Full Text PDFBone Res
January 2025
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Osteoarthritis (OA), the most prevalent degenerative joint disease, is marked by cartilage degradation and pathological alterations in surrounding tissues. Currently, no effective disease-modifying treatments exist. This study aimed to elucidate the critical roles of Myb-like, SWIRM, and MPN domains 1 (MYSM1) and its downstream effector, Receptor-interacting protein kinase 2 (RIPK2), in OA pathogenesis and the underlying mechanisms.
View Article and Find Full Text PDFAm J Hematol
February 2025
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Patients who develop acute myeloid leukemia (AML) after having received treatment for myelodysplastic syndrome (MDS) or related conditions have particularly poor outcomes. This study analyzed adult patients with newly diagnosed AML who previously had MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, and who had received hypomethylating agents, chemotherapy, and/or allogeneic stem cell transplantation (HSCT) for these antecedent disorders. From January 2012 to August 2023, we included 673 patients with a median age of 70 years (range, 19-94); 536 (80%) had transformed from MDS, and the remainder from CMML or MDS-MPN.
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