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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 -
Haematologica Nov 2023
Topics: Humans; Leukemia, Myelomonocytic, Juvenile; Mutation; Signal Transduction; Proto-Oncogene Proteins c-cbl
PubMed: 37226702
DOI: 10.3324/haematol.2022.282385 -
Haematologica Nov 2023Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic...
Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.
PubMed: 37981895
DOI: 10.3324/haematol.2023.283917 -
Journal of Translational Medicine May 2024The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic...
BACKGROUND
The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival.
METHODS
Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs.
RESULTS
K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations.
CONCLUSIONS
Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.
Topics: Humans; Keratin-17; Pancreatic Neoplasms; Tumor Microenvironment; Female; Carcinoma, Pancreatic Ductal; Male; CD8-Positive T-Lymphocytes; Macrophages; Middle Aged; Aged; Receptors, Cell Surface; Antigens, Differentiation, Myelomonocytic; Antigens, CD
PubMed: 38730319
DOI: 10.1186/s12967-024-05252-1 -
Pathobiology : Journal of... 2024Pediatric hematologic malignancies often show genetic features distinct from their adult counterparts, which reflect the differences in their pathogenesis. Advances in... (Review)
Review
Pediatric hematologic malignancies often show genetic features distinct from their adult counterparts, which reflect the differences in their pathogenesis. Advances in the molecular diagnostics including the widespread use of next-generation sequencing technology have revolutionized the diagnostic workup for hematologic disorders and led to the identification of new disease subgroups as well as prognostic information that impacts the clinical treatment. The increasing recognition of the importance of germline predisposition in various hematologic malignancies also shapes the disease models and management. Although germline predisposition variants can occur in patients with myelodysplastic syndrome/neoplasm (MDS) of all ages, the frequency is highest in the pediatric patient population. Therefore, evaluation for germline predisposition in the pediatric group can have significant clinical impact. This review discusses the recent advances in juvenile myelomonocytic leukemia, pediatric acute myeloid leukemia, B-lymphoblastic leukemia/lymphoma, and pediatric MDS. This review also includes a brief discussion of the updated classifications from the International Consensus Classification (ICC) and the 5th edition World Health Organization (WHO) classification regarding these disease entities.
Topics: Adult; Humans; Child; Myelodysplastic Syndromes; Hematologic Neoplasms; Genotype; Germ-Line Mutation; High-Throughput Nucleotide Sequencing
PubMed: 37311434
DOI: 10.1159/000531480 -
Kidney International Reports Dec 2023Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can...
INTRODUCTION
Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can be associated with autoimmune and inflammatory diseases. This study aimed to describe kidney involvement in patients with CMML, their treatments, and outcomes.
METHODS
We conducted a French and American multicenter retrospective study in 15 centers, identifying patients with CMML with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities.
RESULTS
Sixteen patients (males, = 14; median age 76.5 years [71.9-83]) developed a kidney disease 6 months [1.6-25.6] after the diagnosis of CMML. At the time of kidney disease diagnosis, median urinary protein-to-creatinine ratio was 2 g/g [1.25-3.4], and median serum creatinine was 2.26 mg/dl [1.46-2.68]. Fourteen patients (87.5%) underwent a kidney biopsy, and the 2 main pathological findings were lysozyme nephropathy (56%) and renal infiltration by the CMML (37.5%). Ten patients received a new treatment following the CMML-associated kidney injury. Among patients with monitored kidney function, and after a median follow-up of 15 months [9.9-34.9], 4 patients had CKD stage 3, 4 had CKD stage 4, 1 had an end-stage kidney disease. In our patient series, 2 patients evolved to an acute myeloid leukemia (AML), and 5 died. Compared with 116 CMML controls, patients who had a kidney involvement had a higher monocyte count ( < 0.001), had more CMML-1 ( = 0.005), were more susceptible to develop an AML ( = 0.02), and were more eligible to receive a specific hematologic treatment, with hydroxyurea, or hypomethylating agents ( < 0.001), but no survival difference was seen between the 2 groups ( = 0.6978).
CONCLUSION
In this cohort of patients with CMML with a kidney injury, the 2 most frequent renal complications were lysozyme-induced nephropathy and renal infiltration by the CMML. Kidney involvement should be closely monitored in patients with CMML.
PubMed: 38106568
DOI: 10.1016/j.ekir.2023.09.005 -
Frontiers in Immunology 2023Histiocytoses encompass a wide spectrum of diseases, all characterized by tissue infiltration by CD68+ histiocytes. Most adult histiocytoses are considered clonal...
Histiocytoses encompass a wide spectrum of diseases, all characterized by tissue infiltration by CD68+ histiocytes. Most adult histiocytoses are considered clonal diseases because they highlight recurrent somatic mutations in the MAP-kinase pathway gene, primarily . The presence of mutation is associated with widespread disease in children with Langerhans cell histiocytosis (LCH) or cardiovascular/neurological involvement in Erdheim-Chester disease (ECD). Nevertheless, few data are available on adult clonal histiocytosis. This is why we have conducted a retrospective study of all patients with clonal histiocytosis in our institution and present the data according to the presence of mutation. Among 27 adult patients (10 ECD, 10 LCH, 5 Rosai-Dorfman disease (RDD), and 3 mixed ECD/LCH), 11 (39%) have mutation with gain of function (n = 9) and deletion (n = 2). Those patients had frequent multicentric disease with risk organ involvement, especially the brain and cardiovascular system. They had frequent associated myeloid neoplasms (mostly chronic myelomonocytic leukemia) and received more frequently targeted therapy as the front-line therapy. Nevertheless, its presence did not affect the overall survival or relapse-free survival probably due to the emergence of efficient therapies. To conclude, rapid and accurate molecular establishment in adult clonal histiocytoses is crucial because mutation correlates with multicentric disease with organ involvement and incomplete metabolic response.
Topics: Adult; Child; Humans; Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Mutation; Proto-Oncogene Proteins B-raf; Retrospective Studies; Histiocytosis
PubMed: 37809108
DOI: 10.3389/fimmu.2023.1260193 -
Role of monocytes/macrophages in renin-angiotensin system-induced hypertension and end organ damage.Frontiers in Physiology 2023The renin-angiotensin system (RAS) is a central modulator of cardiovascular physiology. Pathophysiology of hypertension is commonly accompanied by hyper-activation of... (Review)
Review
The renin-angiotensin system (RAS) is a central modulator of cardiovascular physiology. Pathophysiology of hypertension is commonly accompanied by hyper-activation of RAS. Angiotensin II receptor blockers (ARBs) and Angiotensin-converting enzyme (ACE) inhibitors are the gold standard treatment for hypertension. Recently, several studies highlighted the crucial role of immune system in hypertension. Angiotensin-II-induced hypertension is associated with low grade inflammation characterized by innate and adaptive immune system dysfunction. Throughout the progression of hypertension, monocyte/macrophage cells appear to have a crucial role in vascular inflammation and interaction with the arterial wall. Since myelomonocytic cells potentially play a key role in angiotensin-II-induced hypertension and organ damage, pharmacological targeting of RAS components in monocyte/macrophages may possibly present an innovative strategy for treatment of hypertension and related pathology.
PubMed: 37854465
DOI: 10.3389/fphys.2023.1199934 -
Journal of Virology Oct 2023Mouse models of viral infection play an especially large role in virology. In 1960, a mouse virus, lactate dehydrogenase-elevating virus (LDV), was discovered and found...
Mouse models of viral infection play an especially large role in virology. In 1960, a mouse virus, lactate dehydrogenase-elevating virus (LDV), was discovered and found to have the peculiar ability to evade clearance by the immune system, enabling it to persistently infect an individual mouse for its entire lifespan without causing overt disease. However, researchers were unable to grow LDV in culture, ultimately resulting in the demise of this system as a model of failed immunity. We solve this problem by identifying the cell-surface molecule CD163 as the critical missing component in cell-culture systems, enabling the growth of LDV in immortalized cell lines for the first time. This advance creates abundant opportunities for further characterizing LDV in order to study both failed immunity and the family of viruses to which LDV belongs, (aka, arteriviruses).
Topics: Animals; Mice; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Culture Techniques; Cell Line; Ectopic Gene Expression; Lactate dehydrogenase-elevating virus; Receptors, Cell Surface; Time Factors
PubMed: 37792000
DOI: 10.1128/jvi.00930-23