Fig. 3

Telomere maintenance in the development of high-risk and low-risk neuroblastoma. a. A model for the growth of NB tumors that belong to different risk groups. Low-risk NB (stage 1, 2, 3 and 4 s) has no TMM; hence, the progressive erosion of telomeres (due to incomplete end replication, telomere trimming, and telomere DNA damage) eventually results in the exhaustion of telomere reserve and loss of proliferative capacity. HR-NB tumors (stage 4) harbor either telomerase or ALT and are able to proliferate indefinitely by counteracting telomere loss. Telomerase-positive NB tumors are faster growing and present predominantly in children, whereas ALT-positive tumors are slower growing and present predominantly in adolescents and young adults. b. A more detailed model on how dynamic changes in telomere trimming activity and telomere maintenance mechanisms during and after oncogenic transformation may influence the growth of NB tumors. The neural crest progenitor cells are proposed to harbor both telomere trimming and telomerase activity. In low-risk NB (green-shaded box), the tumor-initiating cells may either harbor no TMM or turn off telomerase expression in accordance with the developmental program in normal neural crest. The inability to counteract telomere shortening mechanisms leads eventually to short telomeres that are unable to support tumor growth. In contrast, HR-NB can sustain proliferation by either activating TMMs or (in a minority of cases) by repressing telomere trimming completely prior to shutting off telomerase. Low-risk NB spontaneously regress or differentiate when the telomere reserve is insufficient to sustain cell proliferation, whereas high-risk NB tends to progress and cause relapse