Dysregulation of immune cell and cytokine signalling correlates with clinical outcomes in myelodysplastic syndrome (MDS)

Abstract

Novelty Statements: 1.What is the NEW aspect of your work? This study utilises correlative samples collected across 3 prospective clinical trials in MDS conducted in Australia (LEN-SCF, ALLG MDS3 and ALLG MDS4 clinical trials) and uses novel methods for analysing immune cell subsets which correlated with clinical outcomes in MDS. What is the CENTRAL finding of your work?The main findings from this study are that dysregulation in innate immunity and inflammatory signalling play central roles in the pathogenesis of MDS and correlated with clinical responses and maintenance of clinical benefit after 12 months of treatment.3. What is (could be) the SPECIFIC clinical relevance of your work? The genetic and immunological biomarkers identified in this study can help define early markers of resistance to treatment with Azaciditine +/-IMiDs in MDS and future studies should focus on a biomarker-driven approach to guide treatment decisions in patients who may benefit from early escalation of treatment with novel therapies to improve their prognosis.

MicroRNA profiling in aplastic anemia reveals similarities between secondary myelodysplastic syndromes arising from clonal progression and de novo MDS

“…Cytokine-cytokine receptor interactions have been reported as a major pathway enriched in MDS, with miR-221 similarly identified in this study as a key miRNA modulating this pathway, in addition to miR-30b and miR-30e (24). Consistent with this observation, we have previously reported that the gene expression analysis from BM colonyforming units of MDS patients that have normalized after four cycles of treatment, exhibiting the downregulation of cytokine signaling (25).…”

“…Interestingly, Patient No these similar pathways were observed in this study as key regulatory players in driving AA clonal progression to MDS/AML. We have similarly demonstrated that the MAPK12 gene was upregulated at MDS diagnosis and downregulated in normal BM colonies after four cycles of treatment (25). The Hippo signaling pathway interacts with other growth control and cell proliferation pathways such as PI3-AKT, TGF-b, RAS-MAP kinase, JAK/ STAT, Notch, and Wnt signaling through YAP (Yes-associated protein) activation (28), and the downregulation of miR-9 and miR-550-1 is postulated to contribute to AML pathogenesis through inhibition of their tumor suppressor functions on the Hippo and YAP signaling pathways (29,30).…”

Single-cell Multiomics Analysis of Myelodysplastic Syndromes and Clinical Response to Hypomethylating Therapy

“…Related to this proinflammatory milieu that drives the expansion of HSPCs, we have observed that the reduction of nonclassical monocytes is associated with the clinical response to the HMA regimen. Nonclassical monocytes are anti-inflammatory cells that are elevated and functionally impaired in high-risk MDS ( 53, 54 ). Thus, their disbalance might be associated with an overactivation of the proinflammatory signals that will further foster tumor immune escape.…”

Immunophenotypic changes of monocytes in myelodysplastic syndrome and clinical significance

“…It has a chance to transform to AML, leading to a high risk of patient death. Research revealed that the abnormal immunophenotypic changes of bone marrow cells in MDS were tightly associated with the risk stratification of MDS, AML transformation and prognosis [ 20 – 22 ]. CD300e which is expressed by monocytes and mDCs can prevent the apoptosis of these two types of cells by triggering intracellular calcium mobilization and inducing the production of superoxide anion O(2)(-).…”