A morphology-driven proof-of-concept study linking interphase nuclear abnormalities to dicentric-mediated genomic...

Area of Science:

• Hematology
• Cytogenetics
• Oncology

Background:

• Genomic instability drives heterogeneity and treatment resistance in B-cell malignancies.
• Complex karyotypes and TP53 pathway disruption are poor prognostic markers in chronic lymphocytic leukemia (CLL).
• Dicentric chromosomes and structural genomic instability are key features in certain B-cell lymphomas.

Purpose of the Study:

• To investigate if interphase nuclear abnormalities (nucleoplasmic bridges and nuclear buds) on routine blood smears can serve as cytological surrogates for dicentric chromosomes and structural genomic instability.
• To develop and validate a Cytological Instability Score (CIS) for assessing genomic instability in B-cell malignancies.
• To explore the correlation between cytological findings and cytogenetic measures of genomic instability.

Main Methods:

• Analysis of 29 patients with indolent B-cell malignancies (CLL and splenic marginal zone lymphoma) enriched for dicentric chromosomes.
• Development of a semi-quantitative Cytological Instability Score (CIS) based on nucleoplasmic bridges (NPB ≥2%), nuclear buds (NBUD ≥10%), and multinucleated forms in 200 lymphoid cells.
• Measurement of genomic instability using cytogenetics (Charge of Genomic Instability - CGI) and total chromosomal aberrations.

Main Results:

• Nucleoplasmic bridge (NPB) frequency correlated significantly with the Charge of Genomic Instability (CGI) (Spearman rho = 0.89, p < 0.0001).
• Nuclear bud (NBUD) frequency correlated with the total number of chromosomal aberrations (rho = 0.85, p < 0.0001).
• Increasing CIS categories were associated with more complex cytogenetic architectures and rearranged karyotypes.

Conclusions:

• Interphase nuclear morphologies like NPB and NBUD may reflect ongoing breakage-fusion-bridge cycles and underlying structural genomic instability in B-cell malignancies.
• The Cytological Instability Score (CIS) offers a potential morphology-based framework for assessing cytological manifestations of genomic instability.
• Larger validation studies are needed to confirm the reproducibility and clinical utility of the CIS in broader cytogenetic contexts.