Clonality and mutational profiling of a case of composite hairy cell leukemia and chronic lymphocytic leukemia

Abstract

We report a unique case of composite hairy cell leukemia (HCL) and monoclonal B-cell lymphocytosis with chronic lymphocytic leukemia (CLL) phenotype evaluated comprehensively through cell sorting and deep sequencing. The patient presented with decreased exercise tolerance and complete blood count revealed neutropenia, monocytopenia, and thrombocytopenia. The peripheral blood film was suggestive of HCL. However, a bone marrow evaluation was suspicious for composite HCL and CLL. Flow cytometry not only confirmed monoclonal kappa light chain restricted HCL and CLL populations, but also identified a kappa restricted population with co-expression of bright CD20, bright CD22, and CD11c without CD25 or CD103. Each population was isolated by cell sorting and subsequent B-cell receptor gene rearrangement analysis showed distinct rearrangements in each population. Likewise, next-generation sequencing (NGS) showed distinct mutation patterns in each of the monoclonal B-cell populations. The HCL clone harbored the signature BRAF V600E mutation, the CLL clone harbored an RB1 (L343fs*6) mutation, and the third clone was essentially negative for either mutation. In HCL, the BRAF V600E has been found in hematopoietic stem cells, raising the possibility of a common stem cell origin for composite HCL/CLL. However, our findings suggest a process of independent clonal development of multiple neoplastic B-cell populations in composite lymphoma, likely occurring somewhere after the common lymphoid progenitor stage.