Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease

Zhao, Lin; Boy, Maxime; Azoulay, Célia; Clappier, Emmanuelle; Sébert, Marie; Amable, Ludivine; Klibi, Jihène; Benlagha, Kamel; Espéli, Marion; Balabanian, Karl; Preudhomme, Claude; Marceau-Renaut, Alice; Benajiba, Lina; Itzykson, Raphaël; Mékinian, A.; Fain, Olivier; Toubert, Antoine; Fenaux, Pierre; Dulphy, Nicolas; Adès, Lionel

doi:10.1038/s41375-021-01152-1

Cited by 38 publications

(28 citation statements)

References 15 publications

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“…Other inflammatory manifestations associated with MDS with trisomy 8 have been reported less frequently: pyoderma gangrenosum (PG) [56], sweet syndrome (SS) [57], pulmonary alveolar proteinosis [58] and inflammatory arthritis [59]. Moreover, Zhao et al reported a higher incidence of TET2/IDH and SRSF2 mutations in a cohort of MDS/CMML patients with SIADs compared to MDS/CMML patients without, and identified that TET2/IDH and not SRSF2 mutations deeply modified the Treg and CD8+ T-cell subsets distribution [60]. Similarly, Oh et al found a higher incidence of TET2 mutations in a cohort of MDS/CMML patients with SIADs [61].…”

Section: Characteristics Of the Underlying Mdsmentioning

confidence: 99%

Inflammatory and Immune Disorders Associated with Myelodysplastic Syndromes

Jachiet

Fenaux

Sevoyan

et al. 2021

Hemato

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Systemic auto-inflammatory or autoimmune diseases (SIADs) develop in up to a quarter of patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). With or without the occurrence of SIADs, the distribution of MDS subtypes and the international or CMML-specific prognostic scoring systems have been similar between MDS/CMML patients. Moreover, various SIADs have been described in association with MDS, ranging from limited clinical manifestations to systemic diseases affecting multiple organs. Defined clinical entities including systemic vasculitis, connective tissue diseases, inflammatory arthritis and neutrophilic diseases are frequently reported; however, unclassified or isolated organ impairment can also be seen. Although the presence of SIADs does not impact the overall survival nor disease progression to acute myeloid leukemia, they can help with avoiding steroid dependence and make associated adverse events of immunosuppressive drugs challenging. While therapies using steroids and immunosuppressive treatment remain the backbone of first-line treatment, increasing evidence suggests that MDS specific therapy (hypomethylating agents) and sparing steroids may be effective in treating such complications based on their immunomodulatory effect. The aim of this review was to analyze the epidemiological, pathophysiological, clinical and therapeutic factors of systemic inflammatory and immune disorders associated with MDS.

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Section: Characteristics Of the Underlying Mdsmentioning

confidence: 99%

Inflammatory and Immune Disorders Associated with Myelodysplastic Syndromes

Jachiet

Fenaux

Sevoyan

et al. 2021

Hemato

Self Cite

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“…Studies using mouse models have found TET2 loss to be associated with elevated cytokines/chemokines, resulting in increased susceptibility to colitis and IL-1β dependent atherosclerosis [ 14 ]. Additionally, both TET2 and SRSF2, genes involved in pre-mRNA splicing, are associated with systemic inflammatory and autoimmune disease (SIAD), an umbrella term that includes ulcerative colitis and infectious diseases, such as COVID-19 [ 7 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Approximately 30% of CMML patients will have an associated systemic inflammatory and autoimmune disease (SIAD) [ 2 ]. In addition to inflammatory bowel disease, SIAD includes inflammatory arthritis, systemic vasculitis, autoimmune cytopenias, connective tissue diseases, and neutrophilic dermatoses [ 7 ]. Dual CMML and SIAD cases have a higher absolute neutrophil count, a lower proportion of blasts, and a higher frequency of TET2 and SRSF2 mutations in comparison to those with CMML alone [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…We present a case of a 64-year-old male presenting with non-bloody diarrhea, peripheral blood neutrophilia, and monocytosis who was diagnosed with CMML type 0 and ulcerative colitis (UC). UC is one of the systemic inflammatory and autoimmune diseases (SIAD) [ 7 ]. Patients with combined CMML and SIAD exhibit a unique clinical course and response to therapy in comparison to patients with CMML alone [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Coexistence of Chronic Myelomonocytic Leukemia and Ulcerative Colitis With Rapid Progression to Acute Myelomonocytic Leukemia: A Case Report

Pelkey¹,

Graham²,

Zakem³

et al. 2022

Cureus

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Chronic myelomonocytic leukemia (CMML) is a clonal myeloid neoplasm characterized by sustained peripheral blood monocytosis and variable dyspoiesis. We present a case of a 64-year-old male who presented with severe non-bloody diarrhea, peripheral blood neutrophilia, and monocytosis. He was diagnosed with myeloproliferative CMML type 0 and ulcerative colitis (UC). Next-generation DNA sequencing of a bone marrow sample demonstrated mutations of the TET2, ASXL1, NRAS, and SRSF2 genes along with low-level JAK2^V617F mutation. Both TET2 and SRSF2 mutations are associated with systemic inflammatory and autoimmune disease (SIAD), which includes UC. The patient's UC was managed successfully with vedolizumab infusions. The patient’s concurrent CMML was monitored with a “wait and watch” approach. After five months, the patient asymptomatically tested positive for coronavirus disease 2019 (COVID-19). Seven months after his diagnosis of CMML, the patient presented in severe respiratory distress with acute left upper quadrant pain, splenomegaly, and multiorgan failure. A peripheral blood smear demonstrated marked leukocytosis (283 x 10^9 /L) with 39% blasts/promonocytes without Auer rods. The patient was diagnosed with acute myeloid leukemia with myelomonocytic features (AMML). In this report, we discuss the diagnosis of combined CMML and SIAD, mechanisms of immunoregulatory dysfunction that have been suggested to result in CMML progression, and the clinicopathologic significance of the patient’s molecular abnormalities.

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“…For example, loss-of-function mutations in ten-eleven translocation 2 (TET2) were reported to foster unrestrained inflammation and inflammasome priming in response to TLR4 activation and were shown to increase interleukin 1 beta (IL-1β) elaboration, thereby augmenting the proinflammatory bone marrow niche [30]. An available study that depicts the genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune diseases based on next-generation sequencing technology also revealed that common genetic susceptibilities with TET2/IDH mutations may arise in the stem cell compartment with myeloid and lymphoid progeny and participate in the onset and progression of both systemic inflammation and haematological malignancy [31]. In addition to gene mutations, gene expression abnormalities also affect the functions of the corresponding encoded proteins and downstream signalling pathways, and it is already known that Considering the heterogeneous nature of MDS, DE-mRNAs and DE-miRNAs were analysed based on morphological subtypes of MDS.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis on mRNA microarray and microRNA microarray to screen immune-related biomarkers and pathways in myelodysplastic syndrome

et al. 2021

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Background: Myelodysplastic syndrome (MDS) is a haematopoietic malignancy that is characterized by a heterogeneous clinical course and dysplastic maturation of blood lineages. Immune dysregulation has gained attention as one of the fundamental mechanisms responsible for the development of MDS. This study aimed to screen immunerelated biomarkers and pathways in MDS. Methods: Differentially expressed mRNAs (DE-mRNAs) and differentially expressed microRNAs (DE-miRNAs) in different subtypes of MDS were sourced from the Gene Expression Omnibus (GEO) database. DE-mRNAs were intersected with immune-related gene sets to collect immune-related mRNAs, which were put into the Search Tool for the Retrieval of Interacting Genes (STRING) to construct protein-protein interaction (PPI) networks. Target mRNAs of DE-miRNAs were predicted using the miRDB database and intersected with screened immune-related mRNAs to construct miRNA-mRNA interaction networks. Topological analysis of constructed networks was applied to screen key molecules, which were assessed in independent datasets and previous literature. Enrichment analysis was applied to screen dysregulated pathways in MDS. Results: Screened key mRNAs were mainly from the Toll-like receptor (TLR) family, including TLR2, TLR4, TLR7, and from the chemokine family, including C-X-C motif chemokine ligand 10 (CXCL10) and CC chemokine ligand 4 (CCL4). Cytokine-cytokine receptor interactions were among the major pathways in the enrichment analysis results. Hsa-miR-30b, hsa-miR-30e and hsa-miR-221 were validated as key miRNAs and modulate cytokine-cytokine receptor interactions by targeting immune-related mRNAs. Conclusion: Dysregulated cytokines reflect the immunization status in MDS. Immune-related miRNA-mRNA interactions not only provide a perspective to our understanding of immunologic derangement in the pathogenesis of MDS but also provide new therapeutic opportunities.

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Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease

Cited by 38 publications

References 15 publications

Inflammatory and Immune Disorders Associated with Myelodysplastic Syndromes

Inflammatory and Immune Disorders Associated with Myelodysplastic Syndromes

Coexistence of Chronic Myelomonocytic Leukemia and Ulcerative Colitis With Rapid Progression to Acute Myelomonocytic Leukemia: A Case Report

Integrated analysis on mRNA microarray and microRNA microarray to screen immune-related biomarkers and pathways in myelodysplastic syndrome

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