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Kidney Medicine Feb 2024Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy affecting the bone marrow and resulting in peripheral blood monocytosis. Kidney and urinary tract... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy affecting the bone marrow and resulting in peripheral blood monocytosis. Kidney and urinary tract involvement is common and can present dramatically with life-threatening consequences. Kidney involvement can be the result of direct or indirect mechanisms, including prerenal azotemia, glomerular disease, tubulointerstitial involvement, and renovascular disorders. Urinary tract involvement, electrolyte and acid-base disorders, as well as nephrotoxicity from treatment of the disorder can also occur. Given this multifactorial pathogenesis involving several mechanisms concomitantly, nephrologists must exercise heightened awareness and maintain a low threshold for kidney biopsy. There is a pressing need for future research endeavors to elucidate and target the manifestations of CMML that involve the kidneys with the ultimate goal of augmenting overall prognosis and therapeutic outcomes.
PubMed: 38313809
DOI: 10.1016/j.xkme.2023.100769 -
Journal of Clinical Medicine Jan 2024Chronic myelomonocytic leukemia (CMML) is a rare hematologic disorder that infrequently causes acute kidney injury (AKI). CMML can transform into acute myeloid leukemia...
Chronic myelomonocytic leukemia (CMML) is a rare hematologic disorder that infrequently causes acute kidney injury (AKI). CMML can transform into acute myeloid leukemia (AML), which can be accompanied by a deterioration in kidney function. However, severe AKI due to extramedullary manifestations of AML is rare. Herein, we present the case of a 67-year-old male patient with CMML that transformed into AML with severe AKI necessitating hemodialysis. The cause of the AKI was the AML transformation. The patient, with stable kidney function after chemotherapy for CMML, presented with a sudden decline in kidney function. Hemodialysis was initiated because of severe AKI, and histopathologic evaluation of the kidney biopsy specimen revealed severe, diffuse mixed inflammatory cell infiltrates in the interstitium and c-kit-immunopositive myeloblast-like cells. A bone marrow biopsy was performed because of the kidney biopsy findings suggesting that leukemic infiltration led to the diagnosis of AML. The patient received chemotherapy for AML, and his kidney function recovered. As illustrated in this case, severe AKI can develop as an early extramedullary manifestation during transformation from CMML to AML. Therefore, in patients with CMML and rapidly declining renal function, transformation into AML should be considered and histopathologically confirmed by kidney biopsy.
PubMed: 38256628
DOI: 10.3390/jcm13020494 -
Cell Reports Jan 2024The recent proliferation of new Cre and CreER recombinase lines provides researchers with a diverse toolkit to study microglial gene function. To determine how best to...
The recent proliferation of new Cre and CreER recombinase lines provides researchers with a diverse toolkit to study microglial gene function. To determine how best to apply these lines in studies of microglial gene function, a thorough and detailed comparison of their properties is needed. Here, we examined four different microglial CreER lines (Cx3cr1, Cx3cr1, P2ry12, and Tmem119), focusing on (1) recombination specificity, (2) leakiness (the degree of tamoxifen-independent recombination in microglia and other cells), (3) the efficiency of tamoxifen-induced recombination, (4) extraneural recombination (the degree of recombination in cells outside of the CNS, particularly myelo/monocyte lineages), and (5) off-target effects in the context of neonatal brain development. We identify important caveats and strengths for these lines, which will provide broad significance for researchers interested in performing conditional gene deletion in microglia. We also provide data emphasizing the potential of these lines for injury models that result in the recruitment of splenic immune cells.
Topics: Mice; Animals; Mice, Transgenic; Microglia; Integrases; Tamoxifen; Disease Models, Animal
PubMed: 38217856
DOI: 10.1016/j.celrep.2023.113660 -
Bone Marrow Transplantation Apr 2024
Topics: Humans; Prognosis; Cytogenetics; Allografts; Cytogenetic Analysis; Leukemia, Myelomonocytic, Chronic; Hematopoietic Stem Cell Transplantation; Retrospective Studies
PubMed: 38216690
DOI: 10.1038/s41409-023-02184-0 -
Journal of Investigative Medicine High... 2024Ten-eleven translocation 2 () plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional...
Ten-eleven translocation 2 () plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional regulation for inflammatory cytokines, particularly interleukin-6. While loss-of-function mutation in has been associated with hematological malignancies, it has been increasingly recognized to cause atherosclerotic disease. The increased atherogenicity is thought to be the result of increased production of pro-inflammatory interleukin-1β cytokines following activation of NLRP3 inflammasomes. We present a unique case of recurrent atherothrombosis in an elderly man who was diagnosed with chronic myelomonocytic leukemia in the setting of mutation.
Topics: Male; Humans; Aged; Leukemia, Myelomonocytic, Chronic; Epigenesis, Genetic; Mutation; Embolism; Cytokines; Thrombosis; Thromboembolism; DNA-Binding Proteins; Dioxygenases
PubMed: 38214069
DOI: 10.1177/23247096231224366 -
Hematology, Transfusion and Cell Therapy Dec 2023
PubMed: 38199950
DOI: 10.1016/j.htct.2023.11.004 -
Frontiers in Pediatrics 2023This study aimed to investigate the expression patterns and clinical significance of neural cell adhesion molecule-positive (CD56) myelomonocytes in pediatric patients...
OBJECTS
This study aimed to investigate the expression patterns and clinical significance of neural cell adhesion molecule-positive (CD56) myelomonocytes in pediatric patients with moderate aplastic anemia (mAA).
METHODS
Fifty-six pediatric patients with mAA were enrolled in this study. The patients' clinical characteristics, laboratory data, and response to cyclosporine therapy were obtained. CD56 expression on bone marrow myelomonocytic cells was investigated using flow cytometry. The association between aberrant CD56 expression and cyclosporine response was evaluated by a multivariate analysis.
RESULTS
CD56 myelomonocytes were detected in 43% of the mAA cases. Aberrant CD56 expression was frequent on immature CD45CD16 granulocytes and mature CD45CD14 monocytes. Compared with patients with CD56 myelomonocytes (CD56 patients), patients with CD56 myelomonocytes (CD56 patients) were in moderate hematological condition and had a distinct bone marrow cellular composition profile, which included an increased proportion of myeloid cells and CD56 natural killer cells and a reduced proportion of CD4 T cells, CD8 T cells, and B cells. The multivariate analysis determined that CD56 myelomonocytes were a favorable factor for achieving response at 6 months after cyclosporine therapy. There was a trend towards a lower 3-year rate of evolution to severe aplastic anemia or relapse among the CD56 patients (8%) than the CD56 patients (22%).
CONCLUSION
CD56 patients had an increased myeloid compartment and better prognosis compared with CD56 patients. The findings demonstrated the favorable role of CD56 myelomonocytes in aplastic anemia progression.
PubMed: 38152649
DOI: 10.3389/fped.2023.1272593 -
Haematologica Dec 2023Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a...
Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss of function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells (HPCs) also demonstrated sensitivity of SH2B3- mutated HPCs to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
PubMed: 38152053
DOI: 10.3324/haematol.2023.283776 -
The Journal of Biological Chemistry Feb 2024Siglec-7 (sialic acid-binding immunoglobulin-like lectin 7) is a glycan-binding immune receptor that is emerging as a significant target of interest for cancer...
Siglec-7 (sialic acid-binding immunoglobulin-like lectin 7) is a glycan-binding immune receptor that is emerging as a significant target of interest for cancer immunotherapy. The physiological ligands that bind Siglec-7, however, remain incompletely defined. In this study, we characterized the expression of Siglec-7 ligands on peripheral immune cell subsets and assessed whether Siglec-7 functionally regulates interactions between immune cells. We found that disialyl core 1 O-glycans are the major immune ligands for Siglec-7 and that these ligands are particularly highly expressed on naïve T-cells. Densely glycosylated sialomucins are the primary carriers of these glycans, in particular a glycoform of the cell-surface marker CD43. Biosynthesis of Siglec-7-binding glycans is dynamically controlled on different immune cell subsets through a genetic circuit involving the glycosyltransferase GCNT1. Siglec-7 blockade was found to increase activation of both primary T-cells and antigen-presenting dendritic cells in vitro, indicating that Siglec-7 binds T-cell glycans to regulate intraimmune signaling. Finally, we present evidence that Siglec-7 directly activates signaling pathways in T-cells, suggesting a new biological function for this receptor. These studies conclusively demonstrate the existence of a novel Siglec-7-mediated signaling axis that physiologically regulates T-cell activity. Going forward, our findings have significant implications for the design and implementation of therapies targeting immunoregulatory Siglec receptors.
Topics: Antigens, Differentiation, Myelomonocytic; Cell Polarity; Gene Expression Regulation; Ligands; Lymphocyte Activation; N-Acetylglucosaminyltransferases; Polysaccharides; Protein Binding; Signal Transduction; T-Lymphocytes; Humans
PubMed: 38141764
DOI: 10.1016/j.jbc.2023.105579 -
Cancers Dec 2023Myeloid neoplasms and acute leukemias include different entities that have been recently re-classified taking into account molecular and clinicopathological features.... (Review)
Review
Myeloid neoplasms and acute leukemias include different entities that have been recently re-classified taking into account molecular and clinicopathological features. The myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category comprises a heterogeneous group of hybrid neoplastic myeloid diseases characterized by the co-occurrence of clinical and pathological features of both myelodysplastic and myeloproliferative neoplasms. The most frequent entity in this category is chronic myelomonocytic leukemia (CMML) which is, after acute myeloid leukemia (AML), the main myeloid disorder prone to develop cutaneous manifestations. Skin lesions associated with myelodysplastic and myeloproliferative neoplasms include a broad clinical, histopathological and molecular spectrum of lesions, poorly understood and without a clear-cut classification in the current medical literature. The aim of this review is to describe and classify the main clinical, histopathological and molecular patterns of cutaneous lesions in the setting of MDS/MPN in order to improve the diagnostic skills of the dermatologists, hematologists and pathologists who deal with these patients.
PubMed: 38136431
DOI: 10.3390/cancers15245888