In this issue of Blood, use an innovative integrative analyses of mate-pair DNA sequencing (MPseq) and RNA sequencing (RNAseq) to identify recurrent rearrangements of the VAV1 gene and other targetable fusion genes in peripheral T-cell lymphomas (PTCLs). The results could impact the current subclassification of these rare forms of lymphoma and highlight the opportunity for broadening the scope of individualized treatment strategies for patients with T-cell lymphomas.1
Integrated MPseq and RNAseq reveal novel gene fusion transcripts adding to the genomic heterogeneity within PTCL, NOS.
Integrated MPseq and RNAseq reveal novel gene fusion transcripts adding to the genomic heterogeneity within PTCL, NOS.
Recent advances in application of next-generation sequencing technologies to lymphoid neoplasms have led to significant enhancement of our understanding of T-cell lymphomas that may impact the paradigm of classification of PTCLs. Importantly, the entity currently designated as PTCL, not otherwise specified (NOS) exhibits significant heterogeneity at the clinical, histologic, and genetic level and has been considered a “wastebasket” category because of the paucity of understanding of the disease pathogenesis.
According to the 2016 revision of the World Health Organization classification of lymphoid neoplasms,2 the category of PTCL, NOS will require further analysis to refine its components and to identify new clinically relevant diagnostic tools and novel therapeutic targets. Although subtypes of PTCL harbor “disease-defining” genetic aberrations such as ALK-positive anaplastic large cell lymphoma (ALCL), recent next-generation sequencing studies have revealed that other CD30+ T-cell lymphomas (ALCLs and cutaneous CD30+ lymphoproliferative disorders) are genetically heterogeneous. For example, TYK2 rearrangements have recently been identified in CD30+ T-cell lymphoproliferative disorders as well as in ALK-negative ALCLs.3,4 DUSP22 and TP63 rearrangements are present in 30% and 8% of ALK-negative ALCLs, respectively.5
The identification of the novel fusion transcripts in PTCL, NOS by Boddicker et al may have clinical implications. VAV1-GSS, ITK-FER, and IKZF-ERBB4 fusion transcripts could be diagnostic biomarkers that may be assessed through routine laboratory testing approaches such as reverse-transcriptase polymerase chain reaction or fluorescence in situ hybridization. Importantly, these could represent novel therapeutic targets providing an opportunity for individualized treatment.
The identification of the IKZF-ERBB4 fusion transcript in a case of ALK-negative ALCL in conjunction with the recent observation of truncated ERBB4 transcripts creating intronic long terminal repeats in ALK-negative ALCL6 also suggests that ERBB4 may represent a genetic subset of ALK-negative ALCLs and be amenable for therapy using inhibitors that selectively target ERBB-family kinases.
VAV1 rearrangements being observed in both PTCL, NOS and ALK-negative ALCLs1 would suggest that activation of the transcriptional program that induces CD30 expression and anaplastic morphology is independent of VAV1. These findings raise interesting questions for future lymphoma classification systems and may indicate the slow erosion of the categories currently designated as PTCL, NOS and ALK-negative ALCLs.
The findings of Boddicker et al provide cumulative evidence that components of the T-cell receptor signaling pathway are recurrently targeted by genetic alterations in T-cell neoplasm.7 Activating mutations in RHOA (PTCL, NOS and angioimmunoblastic T-cell lymphoma),8 VAV1, ITK, SYK mutations in PTCL, NOS all highlight the potential functional importance of RAC1-mediated effects on cytoskeletal function in T-cell lymphomas.
It is of interest and remains a point of intrigue that although recurrent, the genetic aberrations identified to date in PTCL, NOS represent low-frequency events. These data suggest that even at the genomic level, PTCL, NOS represent a group of highly heterogeneous neoplasms (see figure).
Although the results of the current study extend our understanding of the genomic heterogeneity within PTCL and identify kinase-associated fusion transcripts that may impact patient therapy, future studies will need to elucidate the biologic consequences of VAV1-GSS, ERBB4, and ITK expression. Furthermore, it will be of interest to ascertain how the presence of VAV1 rearrangements or the newly identified gene fusions relate to the recently published gene expression studies that describe overexpression of GATA3, TBX21, and cytotoxic genes in PTCL, NOS.9
Conflict-of-interest disclosure: The author declares no competing financial interests.
