Mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs including embryogenesis, proliferation, differentiation and apoptosis based on cues derived from the cell surface and the metabolic state and environment of the cell. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK(1-3)) and p38(a, b, c and d) families. ERK3, ERK5 and ERK7 are other MAPKs that have distinct regulation and functions. MAPK cascades consist of a core of three protein kinases. Despite the apparently simple architecture of this pathway, these enzymes are capable of responding to a bewildering number of stimuli to produce exquisitely specific cellular outcomes. These responses depend on the kinetics of their activation and inactivation, the subcellular localization of the kinases, the complexes in which they act, and the availability of substrates. Fine-tuning of cascade activity can occur through modulatory inputs to cascade component from the primary kinases to the scaffolding accessory proteins. Here, we describe some of the properties of the three major MAPK pathways and discuss how these properties govern pathway regulation and activity.
Introduction/Objective Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by sustained monocytosis, ranging from cytopenia with a dysplastic subtype to leukocytosis with a proliferative subtype, with a typical mutational profile involving TET2, ASXL1, and SRSF2. Mutation in colony-stimulating factor 3 receptor gene (CSF3R) is commonly associated with chronic neutrophilic leukemia (CNL) but exceedingly rare in CMML, particularly CSF3R T618I (~10 cases described, ~30 cases of CSF3R non-T618I mutations). We report a case of CSF3R T618I mutated CMML and compare the clinicopathologic features to reported CMML cases with and without CSF3R T618I mutations. Methods/Case Report A 27-year-old woman presented for evaluation of leukocytosis, sustained monocytosis, and anemia. Peripheral blood (PB) revealed leukocytosis (white cell count 35x109/L), left-shifted and dysplastic neutrophils (myelocytes and metamyelocytes, 5%), absolute and relative monocytosis (7x109/L, 29%), anemia (Hgb 4.3 g/dL), and thrombocytopenia. Bone marrow aspirate and core biopsy demonstrated a hypercellular marrow with increased myeloblasts (~3%, immunophenotypically aberrant by flow cytometry), increased myelomonocytic cells, and multilineage dysplasia, including ring sideroblasts and hypolobated megakaryocytes. Cytogenetic and molecular studies revealed a normal karyotype and mutations in CSF3R T618I, ASXL1, SETBP1, BCORL1, KRAS, and PTPN11. Despite the presence of a CSF3R T618I mutation, CMML was diagnosed given marked monocytosis, left- shifted neutrophils in PB, multilineage dysplasia, and immunophenotypically aberrant myeloblasts. Results (if a Case Study enter NA) NA Conclusion Our case demonstrates clinicopathological features similar to those of reported CSF3R T618I mutated CMML, i.e., a proliferative subtype and less likely to have co-occurring mutations in TET2 or SRSF2, which is distinct from CSF3R non-T618I mutated CMML; the latter often has a dysplastic subtype and mutational profile of frequent TET2 and SRSF2 mutations, similar to CSF3R unmutated CMML. While additional cases with this unusual mutation need to be studied to arrive at a more definitive conclusion, the CSF3R T618I mutation seems to define a unique proliferative subtype CMML with a distinct mutational profile.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.