Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

Abstract

Key Points• TLR1 is upregulated on primitive AML cells.• Agonistic targeting of TLR1/TLR2 induces apoptosis and differentiation of primitive AML cells in vivo.Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities.Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary MLL-AF9 AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murine AML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined to MLL-rearranged AML.We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects.

E2F4 functions as a tumour suppressor in acute myeloid leukaemia via inhibition of the MAPK signalling pathway by binding to EZH2

“…Subsequent gene ontology analyses indicated that the genes regulated by E2F4 were enriched for the regulation of the MAPK signalling pathway ( Figure 6B). 20,21 To determine the specific mechanism of E2F4-induced tumour cell proliferation and differentiation, we further examined the protein levels of MAPK, p-MAPK, ERK and p-ERK when E2F4 expression levels were manipulated in AML cells. 18,19 The MAPK signalling pathway is also studied in AML.…”

“…18,19 The MAPK signalling pathway is also studied in AML. 20,21 To determine the specific mechanism of E2F4-induced tumour cell proliferation and differentiation, we further examined the protein levels of MAPK, p-MAPK, ERK and p-ERK when E2F4 expression levels were manipulated in AML cells. Knockdown of E2F4 by shRNA significantly decreased the protein levels of p-MAPK and p-ERK compared with those in NB4 and THP-1 cells transduced with NC-shRNA ( Figure 6C).…”

Therapeutic potential of toll‐like receptors in treatment of gynecological cancers

“…They recommend the study of conjugated SLPs in phase I and II safety and immunogenicity of clinical trial . Pam3CSK4, a TLR1 / TLR2 agonist, induces apoptosis in a mouse model of acute myeloid leukemia . In addition, Pam3 CysSK4‐containing compound elicits antitumor activity in in vivo model of mammary cancer .…”

The different roles of toll-like receptors in oncotherapy

“…В случае ТПР3 адаптером служит TRIF (внутриклеточный адаптерный белок, содержащий TIR-домен, включающий интерферон β), связанный с синтезом интерферона (ИФН) 1-го типа. ТПР-регулируемым сигнальным путям активации генов цитокинов и ИФН посвящено множество публикаций [7][8][9][10][11][12][13][14][15][16][17]. Механизмы, связывающие иммунные реакции и воспаление с развитием опухоли, изучены недостаточно.…”