Grant Number:	1R01CA309413-01A1 Interpret this number
Primary Investigator:	Langerak, Anton
Organization:	Erasmus Medical Center
Project Title:	Molecular Detection of Mbl and Enhanced Risk Stratification Through Immunogenetic and Proteomic Profiling.
Fiscal Year:	2026

ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) is a precursor state to chronic lymphocytic leukemia (CLL) affecting up to 5-10% of adults over age 40 in the US. Individuals with MBL are at increased risk of progression to CLL, serious infections, and nonhematological malignancies as well as have reduced humoral immune response to vaccinations. MBL is currently identified through flow cytometry, a labor-intensive and technically demanding approach that requires viable whole-blood cells. The reliance on viable blood cells limits our ability to perform MBL screening in large existing US-based cohorts. Recently, sequencing the immunoglobulin heavy chain (IGH) gene repertoire of the B-cell receptor (BcR) from whole blood DNA has emerged as an alternative approach for identifying premalignant clonality. While this approach allows us to infer the presence of MBL, no study has evaluated the accuracy of IGH gene clonality determined by sequencing of whole blood DNA with MBL status obtained by flow cytometry, the gold standard. Aim 1 seeks to address this critical gap by providing insight into the viability of using IGH gene clonality as a surrogate to flow cytometry. Individuals with MBL are frequently unaware they have MBL, and one of the field’s primary research aims has been to determine which individuals with MBL progress to CLL or other lymphoid malignancy. Cutting edge single-cell sequencing techniques will characterize transcriptome profiles associated with MBL progression and identify somatic mutations contributing to progression. Aim 2 will identify a novel agnostic proteomic MBL signature and evaluate whether proteomic molecular biomarkers associated with CLL risk are also biomarkers for progression among individuals with MBL. Because all individuals with CLL pass through the MBL stage, the next important question is to evaluate how this CLLproteomic signature performs among individuals with MBL. We hypothesize that these CLLproteomic molecular biomarkers will identify which individuals with MBL are at high-risk for progression to CLL or other lymphoid malignancies. Integration of MBL/CLL proteomic markers with MBL/CLL genetic risk loci through Mendelian randomization will reveal the causal effect of MBL/CLL proteomic markers on CLL risk. Collectively, these Aims will leverage our Mayo Clinic MBL cohort of over 10,500 individuals screened for MBL with stored biospecimen. Given its high prevalence, there is critical need to better understand the impact of MBL on human health. To address this need, this application aims to identify molecular factors associated with MBL progression and enable MBL status to be discerned in well established biobanks, facilitating a profound increase in knowledge regarding health implications of a highly prevalent pre-malignant condition in the US. The project outcomes will be of direct relevance to US-based leukemia/lymphoma patients and individuals in the US with MBL, with potential application to other cancer types, as well as providing new research areas for US-scientists. It thereby has the potential to significantly advance the health sciences in the US, as well as the health of individuals with MBL across the entire globe.





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