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

Br J Haematol. 2015 May;169(3):391-400. doi: 10.1111/bjh.13305. Epub 2015 Mar 5.

Abstract

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.

Keywords: JAK2 mutation; chronic lymphocytic leukaemia; customized exome analysis; monoclonal B-cells; monozygotic twins.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Aged
  • Comparative Genomic Hybridization
  • Exome
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunophenotyping
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell / etiology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Lymphocytosis / genetics
  • Male
  • Precancerous Conditions*
  • Somatic Hypermutation, Immunoglobulin
  • Twins, Monozygotic*

Substances

  • Immunoglobulin Heavy Chains