Function of Deptor and its roles in hematological malignancies

Abstract

Deptor is a protein that interacts with mTOR and that belongs to the mTORC1 and mTORC2 complexes. Deptor is capable of inhibiting the kinase activity of mTOR. It is well known that the mTOR pathway is involved in various signaling pathways that are involved with various biological processes such as cell growth, apoptosis, autophagy, and the ER stress response. Therefore, Deptor, being a natural inhibitor of mTOR, has become very important in its study. Because of this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that Deptor can act as an oncogene or tumor suppressor depending on the cellular or tissue context. This review discusses recent advances in its transcriptional and post-transcriptional regulation of Deptor. As well as the advances regarding the activities of Deptor in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.

Keywords: Deptor; Multiple Myeloma; Non-Hodgkin Lymphoma; hematological malignances; leukemia.

Figure 1

Structure of Deptor. Schematic representation of Deptor and his two DEP domains are indicated as well PDZ domain. Degron motif and phosphorylation residues are indicated. phosphorylation at 15 different residues (T and S) located between the DEP2 and PDZ domain junction and comprising between residues T241-S299, which was determined by spectrometric studies, are also indicated.

Figure 2

Transcription factors network involved in the regulation of Deptor. Transcription regulation of Deptor expression by Transcription factors are represented. Transcription factors involved in the regulation of Deptor revised here are shown.

Figure 3

Predicted transcription factors involved in the regulation of Deptor. Predicted transcription factors involved in the Deptor regulation according of bioinformatic analysis using the Jaspar platform (http://jaspar.genereg.net) [52].

Figure 4

microRNAs involved in the regulation of Deptor. Reported microRNAs involved in the regulation of Deptor revised here are shown.

Figure 5

Predicted miRNAs involved in the regulation of Deptor. Schematic representation of predicted miRNAS involved in the Deptor regulation using the database (mirTarBase platform; http://miRTarBase.cuhk.edu.cn/) [143]. A value of p=0.05 for miRNAs whose predicted binding sites in the Deptor 3’UTR region was considerate.

Figure 6

Expression of Deptor in Multiple Myeloma. Oncomine Deptor expression was revised in different reports; (A) Zhan et al, analysis of Deptor Expression. MM shows a higher expression compared to bone marrow cells (*p<0.001). (B) In Carrasco et al, Analysis of Deptor, relationship with disease recurrence and Deptor expression was observed with high Deptor expression compared to non-recurrence (*p<0.05). (C) in Carrasco et al Analysis, we found a moderate high expression of Deptor in Alive patients compared to Dead patients (*p<0.05). (D) in Mullygan et al, analysis shown a responder patient has a moderated high expression of Deptor compared to Non-responders (*p<0.05). (E) In the same data analysis overall survival was shown, and dead patients have an important high expression of Deptor (*p<0.001). (F) Overall survival of patients with MM according to Deptor expression. Number of patients (n) is listed next to the graph (*p<0.05).

Figure 7

Deptor expression in Acute Myeloid Leukemia. Bioinformatic analysis with Oncomine of Deptor expression on AML was revised. (A–C) three different studies by Hafferlach et al, Andersson et al, and Valk et al, were revised and respectively shows an important higher expression of Deptor in patients with AML compared to controls (PBMC and bone marrow) (*p<0.001). (D–G) Metzeler et al, and Raponi et al, analysis shown overall survival status on relationship with Deptor expression (D, G), dead patients have an important high expression of Deptor (*p<0.001). and Progression free survival (E), shows a moderate relationship with high expression of Deptor in dead patients (*p>0.05). (F) Overall survival of patients with AML according to Deptor expression. Number of patients (n) is listed next to the graph (^n/s p>0.05).

Figure 8

Deptor expression in Acute Lymphocytic Leukemia. Oncomine analysis of Deptor expression in ALL was revised. (A) in Coustan Smith et al, expression analysis shows a higher expression in T-ALL vs normal cells and B-ALL (*p=0.05). (B) analysis of minimal residual disease in relationship with Deptor expression, we observed moderate high Deptor expression in patients with positive MRD (*p>0.05). (C) Another study presents by Bhojwani et al, a significant higher Deptor expression was observed in T-ALL compared to B-ALL (*p<0.001), (D) In the same study the Deptor expression was related to recurrence of the disease compared with primary recurrence. Moderate high Deptor expression was related with recurrence (*p<0.05). (E) On the other study presented by Andersson et al, Deptor expression is low in B-ALL compared with Bone Marrow (*p= N/S). (F) On Haferlach et al. study, very low Deptor expression in B-ALL and in B-ALL childhood were observed compared with PBMC (*p= N/S).

Figure 9

Deptor expression in Lymphoma. Based on the Oncomine Analysis we revised Deptor expression in different subtypes of DLBCL lymphoma. (A) in Compagno et al. analysis, we observe a differential expression of Deptor in different subtypes of DLBCL. DLBCL, GCB-DLBCL and ABC-DLBCL, shows higher Deptor expression compared with memory B-cell (*p<0.001). (B) In Shaknovich et al, Analysis, overall survival according Deptor expression was revised, alive patients show slight high Deptor expression compared with dead patients (*p=N/S). (C) in the same analysis two subtypes of DLBCL were revised; ABC-DLBCL vs GC-DLBCL shows a higher Deptor expression in GC-DLBCL (*p<0.05). (D) in the same study recurrence was analyzed and Deptor expression was no significantly high in the patients with recurrence vs patients with no recurrence (*p=N/S).

Figure 10

Deptor expression in Burkitt’s Lymphoma. Oncomine analysis was done to revised Deptor expression in Burkitt’s Lymphoma. (A) in Brune et al, analysis, show high Deptor expression Burkitt’s Lymphoma compared to memory b-cell (*p<0.05). (B) In Hummel et al, shows a moderate high Deptor expression the alive patients at 5 years or at total OS (C) (*p=N/S or *p<0.05 respectively). (D) Overall survival of patients with DLBCL according to Deptor expression. Number of patients (n) is listed next to the graph (^*p>0.01).

Figure 11

Deptor expression in T-cell Non-Hodgkin Lymphoma. Using Oncomine we analyzed Deptor expression on TCL and ALCL. A) a study by Iqbal et al, show high Deptor expression in Adult T-Cell leukemia, Anaplastic Large Cell Lymphoma and Angioimmunoblastic T-cell lymphoma compared with CD4⁺ T cell lymphoma (*p<0.001).

Figure 12

Deptor expression in Hodgkin lymphoma. Deptor expression in Hodgkin Lymphoma was revised by Oncomine analyzes. (A) Hodgkin Lymphoma shown a high Deptor expression. (B) Deptor expression has relationship with stage of the disease, stage IV shown higher Deptor expression compared with stage I (*p<0.05). (C) Deptor expression is higher in dead patients vs alive patients when OS was analyzed (*p<0.05). (D) Relapse timing was related to Deptor expression in refractory is higher Detour expression compare with late relapse timing (*p<0.05).