Wiskott–Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma

Abstract

In T lymphocytes WASP and WIP regulate TCR signaling but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In ALK+ ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased MAPK pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MEK inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.

The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

“…Furthermore, deacetylase-inhibitors TSA and resveratrol also inhibited HLX expression ( Figure 4B), indicating that reported acetylation-mediated nuclear export of STAT3 was also responsible for HLX suppression in treated ALCL cell lines [65]. ChIP-seq data for STAT3 have been generated for ALCL cell line SU-DHL-1 [66], demonstrating binding of STAT3 in the regulatory upstream and downstream regions of HLX (Supplementary Figure 9A). The upstream position has been functionally confirmed in a HL cell line [65], and the downstream position contains a consensus STAT3 binding site (Supplementary Figure 9B), supporting a direct regulatory impact.…”

“…Graphical presentations of the LL-100 data and the generation of a dendrogram via hierarchical clustering by the Ward's method were performed using shinyNGS (https://github.com/pinin4fjords/shinyngs). Chromatin immuno-precipitation (ChIP)-sequencing (seq) data for STAT3 in ALCL cell line SU-DHL-1 were from GEO-dataset GSE117164 [66]. ChIP-seq data for MGA in 293 cells were from ENA-dataset E-MTAB-6006 [70].…”

Assembling nuclear domains: Lessons from DNA repair

“…Indeed, cells derived from patients with WAS have defects in DSB end resection and repair ( Schrank et al, 2018 ). Finally, WASP was recently identified as a tumor suppressor in T cell lymphoma ( Menotti et al, 2019 ). Thus, by driving the formation of nuclear repair domains, WASP may serve an essential tumor suppressor role.…”

Wiskott-Aldrich syndrome protein senses irradiation-induced DNA damage to coordinate the cell-protective Golgi dispersal response in human T and B lymphocytes

“…42 In contrast, underexpression or loss of expression of WASp is linked to hematolymphoid cancers in human subjects. [43][44][45] In the irradiation-induced murine model of cancer, compared with p53 1/2 WASp 1/1 mice, p53 1/2 WASp 2/2 mice have lymphoma. 46 Accordingly, GOLPH3 functions as an oncoprotein, whereas WASp functions as a tumor-suppressor protein, at least in a subset of cancers.…”