Improved classification of leukemic B-cell lymphoproliferative disorders using a transcriptional and genetic classifier.

B-cell chronic lymphoproliferative disorders (B-CLPD) encompass a group of hematologic tumors that often present with leukemic involvement.1 Their heterogeneity and the lack of relatively specific diagnostic markers for most of these diseases make their diagnosis challenging, especially in cases that only have blood involvement or when histology is not available. With the currently used immunophenotypic and molecular markers, around 10% of B-CLPD cases remain unclassifiable and are categorized as B-CLPD, not otherwise specified (B-CLPD, NOS). Few recurrent gene mutations and chromosomal abnormalities have been documented in some entities: BRAF and MYD88 mutations in hairy cell leukemia (HCL) and lymphoplasmacytic lymphoma (LPL), respectively,2,3 in addition to the recurrent 7q31–q32 deletion in splenic marginal zone lymphoma (SMZL).1 However, none of them are diagnostic hallmarks of any particular entity. Gene expression profiling studies have recognized specific signatures that identify most common hematological neoplasms.4,5 Based on these results we postulated that the analysis of the gene expression profiling (GEP) of a large series of leukemic B-CLPD could identify specific signatures for each leukemic disease entity. These signatures could be useful for the classification of cases with undetermined diagnosis (B-CLPD, NOS). In this study, we have investigated the GEP of a large series of leukemic lymphoid neoplasms and identified specific gene signatures for most entities that were validated in an independent cohort. We have also derived and validated a simplified quantitative polymerase chain reaction (qPCR)-based 8-gene assay that reliably recognized these entities and could assist in the diagnosis in routine practice, particularly in atypical cases and B-CLPD, NOS.