The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia

Abstract

Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1–FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to γ-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.

Hes1 expression and CYLD repression are essential events downstream of Notch1 in T-cell leukemia

“…This is the case of human T-ALL carrying mutations in FBW7, the ubiquitin-ligase involved in ICN1 degradation. 7 Another possibility is that Notch activity might not be required to maintain the tumor cells once the leukemia is established; however, our previous work showed that eliminating NFκB by specific hematopoietic deletion of IKKγ was sufficient to induce activation are present in about 50% of T-ALL patients. For this reason, pharmacological γ-secretase inhibitors (GSI) have become an obvious therapeutical opportunity for this type of leukemias.…”

“…5 These mutations cluster in the heterodimerization (facilitating γ-secretase-dependent cleavage) or the PEST domain (increasing ICN1 protein stability). 5,6 Other mutations associated with T-ALL target the Fbw7 ubiquitin ligase that regulates Notch1 degradation 7 further indicating the importance of Notch1 in these human leukemias. On the other hand, murine BM progenitors transduced with ICN1 generate T-ALL leukemias when transplanted into irradiated mice that are characterized by the presence of immature double positive (CD4 + CD8 + ) T-cells in the peripheral blood and the bone marrow of the recipients.…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Missense mutations in NRR domain likely destabilize inhibitor state of NRR domain, allowing ligand‐independent Notch activation 90. PEST domain is involved in proteasomal degradation of NOTCH 91, 92, and truncations lacking PEST region likely impair the degradation of NOTCH and augment Notch activation.…”

Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

“…Not only mutations in NOTCH1 itself can lead to leukemogenesis, cooperating mutations in Notch target genes [19] and regulators (e.g. FBXW7 [20,21] and Ikaros [22][23][24]) have been identified. Mice with germline mutations that inactivate the transcriptional regulator Ikaros (gene symbol Ikzf1) develop T-ALL exclusively [23,25] and the resulting malignancies often have activating NOTCH1 mutations [6,23,24].…”