Therapeutic inhibition of USP7-PTEN network in chronic lymphocytic leukemia: a strategy to overcome TP53 mutated/deleted clones

Abstract

Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091. Treatment of primary CLL samples and cell lines with P5091 induces cell growth arrest and apoptosis, through the restoration of PTEN nuclear pool, both in TP53-wild type and -null environment. Importantly, PTEN acts as the main tumor suppressive mediator along the USP7-PTEN axis in a p53 dispensable manner. In conclusion, we propose USP7 as a new druggable target in CLL.

Inhibition of bromodomain and extra‐terminal proteins increases sensitivity to venetoclax in chronic lymphocytic leukaemia

“…16 In the case of AML, for instance, treatment with BET inhibitors promotes resistance through the up-regulation of BET target genes. 20 Briefly, CLL cells were isolated from peripheral blood samples by density gradient centrifugation accordingly to Ficoll procedure (Sigma-Aldrich). In addition, we have demonstrated the efficacy of BET inhibitors, JQ1, in combination with venetoclax and against venetoclax resistant clone.…”

Reactivating nuclear PTEN to treat CLL

“…Indeed, a small molecule inhibitor of USP7 recently tested in multiple myeloma (MM) pre-clinical models [2] blocks cell cycle progression and induces apoptosis also in CLL cells, similarly to specific USP7 downregulation [1]. Interestingly USP7 inhibition induces apoptosis in a p53-independent manner in CLL.…”

Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53‐dependent apoptosis and anticancer effect

“…1,[4][5][6] Thus, HAUSP plays a crucial role in cell proliferation and differentiation by deubiquitinating MDM2 and PTEN; HAUSP suppression is vital for anticancer therapeutic intervention, simultaneously focusing on HAUSP as a candidate druggable target. [1][2][3][6][7][8] Conversely, the negative regulation of HAUSP exhibits a crucial clinical significance for estimating the prognosis of tumour suppression. [1][2][3][6][7][8] Conversely, the negative regulation of HAUSP exhibits a crucial clinical significance for estimating the prognosis of tumour suppression.…”

“…This finding could be construed as debatable owing to the existence of conflicting results for Hep3B cells, for example, HAUSP-knockdown using siRNA inhibited cell proliferation in Hep3B, and HAUSP inhibition using p5091 also induced apoptosis and cell growth arrest in p53-mutated lymphocytic leukaemia cell line MEC-1 7,8. This finding could be construed as debatable owing to the existence of conflicting results for Hep3B cells, for example, HAUSP-knockdown using siRNA inhibited cell proliferation in Hep3B, and HAUSP inhibition using p5091 also induced apoptosis and cell growth arrest in p53-mutated lymphocytic leukaemia cell line MEC-1 7,8.…”