Licht and Sternberg Figure 1.
Licht and Sternberg Figure 1. Interconnected pathways of survival, proliferation and self-renewal in acute myelogenous leukemia (AML). . / Activating mutations of the Flt3 receptor tyrosine kinase activates the PI 3-kinase pathway and the AKT kinase, leading inhibition of the pro-apoptotic BH3-only protein Bad; this discourages mitochondrial-mediated apoptosis and caspase 9 activation. Activation of AKT also inactivates the Foxo3a transcription factor leading to decreased expression of components of the extrinsic cell death pathway mediated by members of the tumor necrosis factor and their cognate receptors. Activating mutations of the Flt3 kinase, ras or Shp2 protein as well as inactivating mutations of neurofibromin (NF1) leads to activation of the Map kinase pathway, the upregulation of cyclins, decreased expression of cyclin-dependent kinases and increased cell proliferation. Flt3 activation may also encourage cell proliferation by deactivation of transcription factor complexes. The PLZF growth suppressor, which inhibits cell growth by repression of c-myc and cyclin A2, binds to a critical co-factor SMRT. In response to activation of tyrosine kinase pathways, SMRT is phosphorylated, exported from the nucleus and is no longer able to cooperate with PLZF to repress transcription and cell growth. Chimeric transcription factors such as RUNX1-MTG8 and PML-RAR can upregulate components of the Wnt/catenin pathway. Wnt signaling through T cell factor (TCF) transcription factors stimulates myc and cyclin D1 expression as well as other target genes, leading to both proliferation and the ability of the undifferentiated leukemic stem cell to renew itself in the absence of differentiation. The differentiation block in AML may occur by several different mechanisms. Flt3 mutations are associated with decreased C/EBP expression, and Flt3 inhibitors lead to increased expression of that critical myeloid transcription factor. In the case of leukemia associated with RUNX1-MTG8 expression, the fusion protein acts as a dominant negative form of Runx1. Runx1, which is essential for myeloid development, normally synergizes with the C/EBP transcription factors to stimulate myeloid genes. In contrast Runx1-MTG8 blocks C/EBP function and expression and thereby blocks myeloid differentiation. Increased Wnt signaling due to the fusion protein can increase myc expression, which also favors proliferation and self-renewal over differentiation. Runx1-MTG8 can increase expression of TrkA, potentially contributing to cell proliferation. / Green arrows = stimulatory pathways. Red lines = inhibitory pathways.

Interconnected pathways of survival, proliferation and self-renewal in acute myelogenous leukemia (AML).

Activating mutations of the Flt3 receptor tyrosine kinase activates the PI 3-kinase pathway and the AKT kinase, leading inhibition of the pro-apoptotic BH3-only protein Bad; this discourages mitochondrial-mediated apoptosis and caspase 9 activation. Activation of AKT also inactivates the Foxo3a transcription factor leading to decreased expression of components of the extrinsic cell death pathway mediated by members of the tumor necrosis factor and their cognate receptors. Activating mutations of the Flt3 kinase, ras or Shp2 protein as well as inactivating mutations of neurofibromin (NF1) leads to activation of the Map kinase pathway, the upregulation of cyclins, decreased expression of cyclin-dependent kinases and increased cell proliferation. Flt3 activation may also encourage cell proliferation by deactivation of transcription factor complexes. The PLZF growth suppressor, which inhibits cell growth by repression of c-myc and cyclin A2, binds to a critical co-factor SMRT. In response to activation of tyrosine kinase pathways, SMRT is phosphorylated, exported from the nucleus and is no longer able to cooperate with PLZF to repress transcription and cell growth. Chimeric transcription factors such as RUNX1-MTG8 and PML-RAR can upregulate components of the Wnt/catenin pathway. Wnt signaling through T cell factor (TCF) transcription factors stimulates myc and cyclin D1 expression as well as other target genes, leading to both proliferation and the ability of the undifferentiated leukemic stem cell to renew itself in the absence of differentiation. The differentiation block in AML may occur by several different mechanisms. Flt3 mutations are associated with decreased C/EBP expression, and Flt3 inhibitors lead to increased expression of that critical myeloid transcription factor. In the case of leukemia associated with RUNX1-MTG8 expression, the fusion protein acts as a dominant negative form of Runx1. Runx1, which is essential for myeloid development, normally synergizes with the C/EBP transcription factors to stimulate myeloid genes. In contrast Runx1-MTG8 blocks C/EBP function and expression and thereby blocks myeloid differentiation. Increased Wnt signaling due to the fusion protein can increase myc expression, which also favors proliferation and self-renewal over differentiation. Runx1-MTG8 can increase expression of TrkA, potentially contributing to cell proliferation.

Green arrows = stimulatory pathways. Red lines = inhibitory pathways.

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