NOTCH1 Is Targeted by Ig Translocations in NHL.

NOTCH1 signaling is required for normal T cell development. Its aberrant activation by either the rare t(7;9) translocation or frequent mutation(s) in T-ALL points to an important role of this gene in T cell lymphomagenesis. So far, a pathogenetic role for NOTCH1 in B-cell malignancies is unknown. We report here evidence for NOTCH1 rearrangements in B-cell lymphoma. Two novel 9q34 translocations involving either the 14q32/IGH or the 22q11/IGL locus were identified in 2 patients with respectively, Richter syndrome (RS) and follicular lymphoma (FL). The first case showed a clone with a sole trisomy 12 detected by FISH in 25% of interphase cells and a subclone with an additional dic(9;14)(q34;q32) in 60% of cells from a lymph node sample. The karyotype of the FL case was characterized by the typical t(14;18)(q32;q21)/IGH-BCL2 accompanied by additional t(8;14)(q24;q32)/IGH-CMYC and t(9;22)(q34;q11). FISH analysis of dic(9;14) and t(9;22) using a set of BAC clones mapped both 9q34 breakpoints to the 5′end of NOTCH1. These breakpoints were different from the breakpoint of t(7;9)(q35;q34) (intron 24), as demonstrated by FISH analysis of the T-ALL SUPT1 cell line. NOTCH1 rearrangements showed to be rare in B-NHL. Any of the additional 30 lymphoma cases with structural aberrations of 9q34 analyzed by FISH showed rearrangement of this gene. So far, aberrant activation of NOTCH1 in the reported cases with dic(9;14) and t(9;22) could not be documented: both lymphomas but also 9 control CLL and FL cases without 9q34 aberrations revealed expression of NOTCH1 mRNA by RT-PCR, its ligand JAGGED2 and its transcriptional target HES1. This expression pattern indicates a ligand-driven NOTCH1 signaling in all analyzed cases, possibly reflecting its physiological activation in progenitor B cells and thus, masking the presumed aberrant activation of NOTCH1 in present lymphomas. Whether IGH/L-NOTCH1 translocations in B-NHL lead to the generation of truncated/activated NOTCH1 proteins, similar to these found in T-ALL, remains to be determined. Particularly interesting is the association of the dic(9;14) with Richter transformation in the first case suggesting that rearrangement of NOTCH1 could be responsible for a rapid progression of the underlied CLL. In the second case of FL, t(9;22) seemed to be associated with the evolution of t(14;18)-positive karyotype. These findings contrast with t(7;9), considered as a primary oncogenic event in development of T-ALL. Further molecular and immunohistochemical investigations of the reported cases are in progress.