This report describes a primary gastric ALK-positive B-lineage lymphoma in which a clathrin (CLTC)-ALK fusion was identified by RT-PCR and direct sequencing of the breakpoint.
The initial identification of the ALK gene, expressed as C-terminal part of the transforming fusion protein NPM-ALK in the t(2;5)(p23;q35)lymphoma-associated chromosomal translocation, revealed a novel receptor tyrosine kinase (RTK).
Diffuse large B-cell lymphoma (DLBCL) with plasmablastic features associated with t(2;17)(p23;q23) and characteristic granular cytoplasmic anaplastic lymphoma kinase-1 (ALK1) protein expression is a rare lymphoma subtype.
Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma.
These results suggest that lymphomas carrying variants of the NPM-ALK fusion protein can be detected by immunostaining for ALK and NPM and also that they can be grouped with classical t(2;5)-positive tumors as a single entity (ALK-positive lymphoma or "ALKoma") that shows a better prognosis than ALK-negative anaplastic large-cell lymphoma.
Whilst the strong labelling for phosphotyrosine observed in the lymphoma cells is due to the presence of activated ALK, the strong staining of some normal cells presumably represents physiologically active kinases and this should be taken into account when interpreting the immunostaining of non-lymphoid tumours.
The term ALKlymphoma signifies a switch in the use of the diagnostic criteria: cases are selected on the basis of a genetic abnormality (the ALK rearrangement), instead of the review of morphological or immunophenotypical features which are clearly more prone to disagreement and controversy.
No such "signalosome" is found in rafts of ALK(+) T lymphoma and Hodgkin-derived cell lines, despite similar Cbp/PAG, Lyn, and STAT3 expression and similar amounts of raft sphingolipids.
These 2 cases, therefore, represent a hitherto undescribed mechanism of ALK activation in lymphoma and further illustrate the diversity of fusion partners for the ALK gene.
These findings provide further evidence of the breakpoint heterogeneity in ALK translocations and highlight the importance of ALK immunostaining in the diagnosis of ALCL and the identification of the underlying genetic abnormalities in this lymphoma.
These findings represent the first recurrent translocation reported in ALK-negative ALCL and highlight the utility of massively parallel genomic sequencing to discover novel translocations in lymphoma and other cancers.
Clinically, cutaneous ALK+ ALCL can be divided into primary (cutaneous forms) and the much more common, secondary dissemination by a systemic lymphoma.
Our data argue against PDGFRB activation in association with ALK gene aberrations in metastatic NSCLC and thus seem to imply differential pathobiological roles of ALK alterations in lung cancer and lymphoma, possibly depending on different fusion partner genes.
Importantly, antagonizing SUMOylation by the SENP1 protease decreased the accumulation of NPM-ALK and suppressed lymphoma cell viability, proliferation, and anchorage-independent colony formation.
The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer.
Thus, our results show (1) that NPM-ALK and TPM3-ALK oncogenes are sufficient for lymphoma/leukemia development and required for tumor maintenance, hence validating ALK as potentially effective therapeutic target; and (2) for the first time, in vivo, the equal tumorigenic potential of the NPM-ALK and TPM3-ALK oncogenic tyrosine kinases.
Once a diagnosis of lymphoma is established, it is important to exclude systemic anaplastic lymphoma kinase-negative ALCL involving the breast, primary cutaneous ALCL, and other CD30(+) lymphoproliferative disorders.