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 Updated on: Jan 9 2014

Normal cell counterpart

Normal cell counterpart; differential characteristics between neoplasia cell and its normal counterpart

 

 

Subject

The study of myeloma and normal B cell biology provides important information that reflects the abnormal development of the cellular component of lymphoid malignancies. It is envisioned that we can now achieve a molecular classification of myeloma that provides greater information than traditional clinical data sets. Studying the relationship of myeloma plasma cells to their normal counterparts is essential to identifying tumour specific targets

 

Present status

The cell of origin in MM: Myeloma cells characteristically display somatically mutated Ig V genes, and it is the pattern of these mutations, which has provided insight into the stage of neoplastic arrest. Analysis of multiple tumour-derived clones has shown that there is intraclonal homogeneity of V gene sequences. This is compatible with a neoplastic transformation occurring at a stage when somatic mutation has ceased, commensurate with a post-follicular or post-germinal centre origin.

 

Even in typical isotype switched MM, there is evidence from V genes for tumour-derived variant V(D)J-Cm transcripts in some cases. This both implicates the stage of isotype switch in tumour origins, compatible with the high incidence of chromosome 14q32 translocations into switch regions, and raises the possibility of an earlier, less differentiated cell which may be the precursor entity feeding the tumour population. Observations supporting the view that less mature B-cells are the stem cell of myeloma as well as those indicating that clonal B-cells are only an epiphenomenon have been published, but this issue remains unresolved. However, this question is a crucial one in relation to therapy aimed at the fully differentiated plasma cell; as such a feeder cell may then lie outside the scope of treatment being considered.

 

The combined clinical, pathological, genetic and phenotypic observations indicate a stepwise model of multiple myeloma progression. It has been proposed that the first immortalizing oncogenic event in the germinal centre, most frequently is a primary IgH translocation occurring at the time of switch recombination and somatic hypermutation. The primary Ig translocation results in the ectopic expression of an oncogene that causes proliferation of the long-lived plasmablast/plasma cell. Secondary translocations seem to contribute to subsequent progression associated with increased proliferation, mutations of ras and p53 and dysregulate c-MYC.

 

A more detailed knowledge of normal and neoplastic plasma-cell biology and the microenvironment might allow us to develop specific inhibitors useful in therapy.

 

Role of the microenvironment: (see area B4.0.1.4)

 

Immortalization and Malignant Transformation: (see area B4.0.1.5).

 

Preview of Programme Proposed

Through traditional molecular genetic and novel genomic techniques, several targets have been identified that could contribute to pathogenesis of myeloma. New initiatives are required, however, to advance models and systems with which to validate these targets as having causal or critical relationships to the proliferation or survival of myeloma plasma cells.


Applying new technologies can help generate and test the capacity of the in vitro models to accurately mimic clinical disease. Standardizing such model systems will provide the reagents necessary for achieving a systematic understanding of the biochemical signalling pathways that contribute to pathogenesis. It is envisioned that the EUMMNE community will share such model systems through this proposal. This will provide for a systematic and comparative evaluation of the molecular definitions of MM, using integrative molecular technologies by:

  • Generate cDNA archives from flow-sorted single B cell of the hierarchical subsets

  • Develop and apply a panel of quantitative RT-PCR analysis of adherence molecules, differentiation antigens, chemokine receptors, growth factor receptors, early and late oncogenes, proto-oncogenes and resistance genes

  • Use high-throughput RNA and protein expression technologies for 
    comprehensive molecular analyses to gain insight into neoplastic 
    alterations in biochemical pathways and immune function

  • Analyse differences and similarities between neoplastic cells and their presumed normal counterparts

  • Study the genomic events in tumor evolution via longitudinal analyses of cells in patients with well-characterised disease presentation.

 

Deliverables and Cooperations

This programme must make use of other proposed initiatives involving shared tissue and clinical data resources in order to: 

  • Develop a comprehensive molecular definition of myelomagenesis and 
    normal lymphoid differentiation;
     
  • Use insights from improved understanding and molecular definitions of human lymphoid malignancies to create and validate animal models

  • Develop a novel in vitro model for B cell differentiation to be used for all B cell malignancies.

 

This part of the project is fully dependent on the special PCR systems, FISH and cDNA microarray facilities established within the EUMMNE project. An ongoing coordination with B.4.0.1.2,-3,-4, and -5 will be organized to maximize the speed and efficiency of this part.

 

B.4.0.2.1, -2 and B.4.0.3.1 are expected to benefit directly from this part of the project.

 

Beyond 18 months the goal is to develop a coordinated strategy to define oncogenesis and to initiate a coordinated effort to perform a common research program between the participants in this area. 

Secr. Hans E. Johnsen | Depart. of Haematology | Aalborg University Hospital | Sdr. Skovvej 15 | DK-9000 Aalborg | Denmark | T:+45 9766 3871 | F:+45 9766 6369