Nature and nurture: a case of transcending haematological pre-malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B-cell proliferations.
We describe a comprehensive molecular analysis of a pair of monozygotic twins, who came to our attention when one experienced amaurosis fugax and was diagnosed with JAK2+ polycythaemia vera. He (Twin A) was also found to have an asymptomatic B-cell chronic lymphocytic leukaemia (B-CLL). Although JAK2-, Twin B was subsequently shown to have a benign monoclonal B-cell lymphocytosis (MBL). Flow cytometric and molecular analyses of the B-cell compartments revealed different immunoglobulin light and heavy chain usage in each twin. We hypothesized that whole exome sequencing could help delineating the pattern of germline B-cell disorder susceptibility and reveal somatic mutations potentially contributing to the differential patterns of pre-malignancy. Comparing bone marrow cells and T cells and employing in-house engineered integrative analysis, we found aberrations in Twin A consistent with a myeloid neoplasm, i.e. in TET2, RUNX1, PLCB1 and ELF4. Employing the method for detecting high-ranking variants by extensive annotation and relevance scoring, we also identified shared germline variants in genes of proteins interacting with B-cell receptor signalling mediators and the WNT-pathway, including IRF8, PTPRO, BCL9L, SIT1 and SIRPB1, all with possible implications in B-cell proliferation. Similar patterns of IGHV-gene usage to those demonstrated here have been observed in inherited acute lymphoblastic leukaemia. Collectively, these findings may help in facilitating identification of putative master gene(s) involved in B-cell proliferations in general and MBL and B-CLL in particular.
Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
Marcus C
MC
Hansen
Charlotte G
CG
Nyvold
Anne S
AS
Roug
Eigil
E
Kjeldsen
Palle
P
Villesen
Line
L
Nederby
Peter
P
Hokland
D000368:Aged; D055028:Comparative Genomic Hybridization; D059472:Exome; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D008218:Lymphocytosis / Q000235:genetics; D008297:Male; D011230:Precancerous Conditions; D027041:Somatic Hypermutation, Immunoglobulin; D014430:Twins, Monozygotic
D007143:Immunoglobulin Heavy Chains
JAK2 mutation; chronic lymphocytic leukaemia; customized exome analysis; monoclonal B-cells; monozygotic twins