Distinct patterns of bone marrow complement and immunoglobulin deposition define unique clinicopathologic phenotypes in myelodysplastic neoplasms Free

Background: Immune dysregulation and complement activation are implicated in bone marrow failures, but their specific roles in myelodysplastic neoplasms (MDS) remain poorly characterized. We investigated the prevalence and extent of complement and immunoglobulin deposition in an MDS cohort and correlated these findings with clinical, hematologic, and molecular features.

Methods: We performed a comprehensive analysis of 44 MDS patients. Bone marrow trephine biopsies underwent immunohistochemistry (IHC) for C3, C4d, IgG, and IgM, graded from 0 to 3. Clinical and laboratory data at diagnosis and biopsy were collected as medians and interquartile ranges. Myeloid next-generation sequencing was performed on all patients. Statistical associations were evaluated using non-parametric tests. Firth's penalized logistic regression was used to build multivariate models.

Results: Deposition of C3 and C4d was observed in 42 (96%) and 39 (89%) patients, respectively. High-grade (2-3) C3 deposition (n=24, 55%), compared to low or no (0-1) deposition (n=20, 45%), was associated with more severe cytopenias, including lower hemoglobin levels at diagnosis (9.1 vs. 10.1 g/dL; p=0.06) and lower platelet counts (111 vs. 196 x10⁹/L; p=0.08), andwith a younger age at evaluation (78 vs. 81 years; p=0.12). It was also associated with a higher rate in SF3B1-mutated and hypoplastic (38% vs. 20% and 12.5% vs. 0%; p=0.08, respectively) WHO-2022 MDS subtypes, a larger marrow lymphoid infiltrate (7.5% vs. 5%; p=0.08), and a broader deposition pattern on megakaryocytes and/or erythroid colonies (48% vs. 17%; p=0.02). Similarly, high-grade (2-3) C4d deposition (n=19, 43%) was linked to lower hemoglobin (8.1 vs. 9 g/dL; p=0.07) and platelet counts (114 vs. 218 x10⁹/L; p=0.26), significantly higher rates of RBC-transfusion-dependence (79% vs. 44%; p=0.02), and worse IPSS-R (58% vs. 24% intermediate; p=0.075) and IPSS-M (60% vs. 25% moderate-low/high; p=0.05) risk categories. This group also had a higher frequency of erythropoiesis-stimulating agent exposure (68% vs. 44%; p=0.11), marrow reticulin fibrosis (37% vs. 12%; p=0.07), and systemic complement activation, with lower serum C3 (69 vs. 82 mg/dL; p=0.03) and C5 (15 vs. 21 mg/dL; p=0.05) levels.

IgM and IgG deposition were present in nearly all patients(n= 43, 98%). High-grade (3) IgM deposition (n=28, 64%) was associated with significantly lower platelet (112 vs. 201 x10⁹/L; p=0.04) and lymphocyte (1.2 vs. 1.7 x10⁹/L; p=0.06) counts, a higher frequency of autoimmune comorbidities (36% vs. 13%, p=0.16), a lower frequency of SF3B1 mutation (82% vs. 50%; p=0.04), and a non-hypercellular marrow (47% vs. 6%; p=0.005), with deposition scattered to megakaryocytes and/or erythroid colonies (48% vs. 17%; p=0.02).

High-grade (3) IgG deposition (n=23, 52%) was associated with a milder decrease in platelets (118 vs. 180 x10⁹/L; p=0.12), lower median cellularity ( 50% vs 70%; p=0.15), a higher frequency of lymphoid infiltrate (96% vs. 71%; p=0.04), and a broader IgG deposition pattern, extended to megakaryocytes, erythroid colonies, and/or mononucleate cells (91% vs. 60%; p=0.02); additionally, IgG deposition was associated with a significantly lower mortality rate (35% vs. 67%; p=0.035).

Spearman correlation analysis confirmed strong correlations between C3 and C4d (p=0.005) and between IgG and IgM deposits (p=0.001). Multivariate analyses lacked significant predictors due to limited sample size, emphasizing the need for larger validation cohorts.

Conclusions: Complement and immunoglobulin deposition on bone marrow precursors are present in nearly all MDS patients. High-grade C4d deposition is associated with transfusion-dependent anemia and systemic complement consumption, IgM deposits are linked to a non-SF3B1 subtype with thrombocytopenia, whereas high-grade IgG deposition correlates with hypocellularity, lymphoid infiltrate, and improved survival. Further investigation is needed to assess the potential impact of complement activation in MDS pathogenesis and its relevance as a promising therapeutic target.