Blood biomarkers are altered in elderly hematological patients exhibiting a mosaic loss of the Y chromosome in bone marrow cells.

BACKGROUND

Mosaic loss of the Y chromosome (LOY) is a frequent somatic alteration observed in aging males, linked to clonal hematopoiesis and elevated risks of hematologic malignancies. However, the direct physiological implications of LOY in elderly patients with hematologic disorders remain unclear. We investigated blood biomarker changes associated with LOY in elderly male patients with hematologic malignancies.

METHODS

We retrospectively analyzed 196 elderly male patients (median age, 71 years) with LOY detected via bone marrow karyotyping (2017-2022). Participants were stratified into four groups: no disease (n = 22); acute myelogenous leukemia, myelodysplastic syndrome (including refractory anemia [RA], refractory anemia with excess blasts [RAEB], and RAEB in transformation [RAEB-T]), chronic myelomonocytic leukemia (CMML) (AML/MDS group, n = 52); multiple myeloma (MM, n = 37); and chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL) (CLL/lymphoma group, n = 85). Controls (n = 120) exhibited normal 46,XY karyotypes. Blood markers (n = 22)-including blood cell counts, cytokines, immunoglobulins, and thyroid hormones-were assessed using non-parametric tests and multivariate regression analysis.

RESULTS

LOY was detected in 4% of patients (3% pure LOY, 1% LOY with additional abnormalities). AML/MDS patients with LOY were younger (median 68.5 vs. 75.5 years in no-disease, p = 0.004) and exhibited higher LOY burden (60% vs. 33% in CLL/lymphoma, p < 0.001). Multivariate analysis revealed age as an independent risk factor for AML/MDS (p = 0.002), while LOY burden specifically correlated with CLL/lymphoma (p = 0.012). Distinct biomarker profiles emerged: LOY-positive AML/MDS patients showed reduced hemoglobin, platelets, and cytokines (e.g., reduced interleukin-2, interferon-gamma) versus controls (p < 0.05), whereas CLL/lymphoma cases correlated with decreased immunoglobulins (IgM) and cytokines (e.g., interleukin-4, interleukin-17 A). Notably, individuals without hematologic disease exhibited stable biomarker profiles irrespective of LOY status, suggesting context-dependent effects of LOY. A high LOY burden (≥ 75%) was associated with cytopenias in AML/MDS, characterized by decreased white blood cell (WBC) count, neutrophil count (NEC), and platelet (PLT) count (p < 0.05).

CONCLUSION

LOY exhibits disease-specific associations with immune-metabolic dysregulation, particularly in AML/MDS and CLL/lymphoma. Its varying burden and biomarker profiles suggest potential utility in risk stratification, warranting further prospective validation.