Jianbiao Zhou

Immunoglobulin gene segment usage, location and immunogenicity in mutated and unmutated chronic lymphocytic leukaemia.

The mutational status of the variable region of the immunoglobulin heavy chain gene (IgVH) is an important prognostic marker in B‐cell chronic lymphocytic leukaemia (B‐CLL), with mutated patients having improved outcome. To examine the impact of mutational status on VH, DH, and JH gene segment location and immunogenicity, we analysed 375 IgH sequences from 356 patients with B‐CLL. Although VH and DH gene usage was different in mutated compared to unmutated patients, there was no impact of gene location on frequency of use or clinical outcome. Surprisingly, somatic mutations did not increase the immunogenicity of the Ig, as assessed by predicted binding affinity of Ig‐derived peptides to major histocompatibility Class I and Class II molecules. Even excluding patients using VH1‐69, cases using the VH1 gene family had a poor outcome. Both mutated and unmutated CLL patients demonstrated evidence of antigen selection. The worst outcome was seen in the subset of 14 unmutated patients with similar HCDR3 amino acid sequence using VH1‐69, DH3‐3 and JH6, suggesting an antigen‐driven process modulating the clinical course.

THE ROLE OF THE TUMOR MICROENVIRONMENT IN HEMATOLOGICAL MALIGNANCIES AND IMPLICATION FOR THERAPY

The tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion, and metastasis by providing survival signals and a sanctuary site for tumor cells, by secretion of growth factors, pro-angiogenesis factors and direct adhesion molecule interactions. Our knowledge of microenvironment is only now beginning to unfold. In this review, the morphological and molecular characteristics of microenvironment in various hematological malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, lymphoma, chronic lymphocytic leukemia, and multiple myeloma are summarized and the molecular mechanisms of microenvironment contributing to leukemogenesis are elucidated. We also aim to discuss the encouraging preclinical and clinical trials for treatment of hematological malignancies by targeting the tumor microenvironment. Further understanding of the signal transduction pathways between tumor cells and microenvironment will lead to the development of novel targeted therapeutic agents and more effective combination of current drugs for fighting hematological malignancies.

Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias

Infant acute lymphoblastic leukaemia (ALL) represents a rare but unique subset with poor prognosis. We analysed mixed‐lineage leukaemia (MLL) gene rearrangements and the sequences of complete and incomplete immunoglobulin heavy chain gene rearrangements (IGH) in 14 infants (age ≤12 months at diagnosis) enrolled on Dana‐Farber Cancer Institute ALL Consortium Protocol 95–01. The dynamics of the leukaemic clone were followed during the course of the disease by quantitative real‐time polymerase chain reaction of IGH rearrangements. Sixteen sequences were obtained from 13 (93%) of these infants. There was marked over usage of the VH6.1 gene segment (64%) in infants compared with older children with ALL (8%), (P < 0·001) and overusage of DH6 (P = 0·004) and JH1 (P = 0·004). Poor outcome was associated with MLL gene rearrangements rather than any specific VHDHJH gene usage patterns. Levels of minimal residual disease (MRD) at the end of induction appeared to be high in infants with ALL compared with older children, and although the number of infant cases studied was small, there were no differences in MRD levels after induction therapy in infant ALL with or without MLL gene rearrangements (P = 0·41) and quantitative MRD assessment at the early time points may not be predictive of outcome. Novel treatment strategies are required to improve the outcome in this poor prognosis subset of children with ALL.