Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

Abstract

Although the Myc transcription factor has been shown necessary for the oncogenic function of Ras, the contribution of Ras pathway signaling to the oncogenic function of Myc remains unresolved. We report the novel findings that Myc alone induced Ras/Mapk pathway signaling, and increased signaling following growth factor stimulation. Deletion of the scaffold protein kinase suppressor of Ras 1 (Ksr1) attenuated signaling through the Ras/Mapk pathway, including activation following Myc induction. B cells that lacked Ksr1 exhibited reduced proliferation and increased cytokine deprivation-induced apoptosis. Overexpression of Myc rescued the proliferation defect of Ksr1-null B cells, but loss of Ksr1 increased sensitivity of B cells to Myc-induced apoptosis. Notably, there was a significant delay in lymphoma development in Ksr1-null mice overexpressing Myc in B cells (El-myc transgenic mice). There was an elevated frequency of p53 inactivation, indicative of increased selective pressure to bypass the p53 tumor suppressor pathway, in Ksr1-null El-myc lymphomas. Therefore, loss of Ksr1 inhibits Ras/Mapk pathway signaling leading to increased Myc-induced B-cell apoptosis, and this results in reduced B-cell transformation and lymphoma development. The c-Myc transcription factor is an oncoprotein that is frequently overexpressed in hematological malignancies through translocations, amplifications, and other less characterized mechanisms. Overexpression of Myc, which drives cell cycle progression, is a well-characterized initiating step in human Burkitt's lymphoma, a non-Hodgkin's B-cell lymphoma. The role of Myc in non-Hodgkin's B-cell lymphoma was established in part by the Em-myc transgenic mouse model that overexpresses Myc in B-cells and develops pre-B/B-cell lymphoma. 1 Overexpression of Myc in primary B cells triggers activation of the Arf-Mdm2-p53 tumor suppressor pathway, which leads to apoptosis. Specifically, Myc induces Arf, which inhibits Mdm2, causing p53 activation and B-cell apoptosis. Myc-overexpressing B cells that acquire mutations that inhibit apoptosis survive and can be transformed. This is exemplified in that 80% of the lymphomas that arise in Em-myc mice have deleted Arf, overexpress Mdm2, or have mutated or deleted p53, all of which inhibit Myc-induced apoptosis. 2 Similar observations have been made in human lymphomas. [3][4][5] Therefore, whereas Myc overexpression induces B-cell transformation in vivo, it requires B cells to gain resistance to apoptosis induced by the hyperproliferative signals from Myc for this to occur.The Ras-Raf-Mek-Mapk/Erk (Ras/Mapk) signaling pathway is essential for cell growth, differentiation, and cell survival. 6 Kinase suppressor of Ras 1 (Ksr1) was first identified as a positive modulator of Ras signaling in genetic screens of Drosophila and C. elegans. 7 Subsequent studies have shown Ksr1 functions as a scaffold protein that can bind and facilitate signaling of multiple components of the Ras/Mapk signaling pathway. 6 Deletion of Ksr1 results in decreased Mapk-Erk1/2 ...

MYC as therapeutic target in leukemia and lymphoma

“…154 More recently, it has been shown that the impairment of RAS-MAPK pathway in mice deficient for KSR1 gene (encoding a scaffold protein of MAPK) results in a decrease in Myc-induced lymphomagenesis in a murine model. 155 …”

Critical role of SHP2 (PTPN11) signaling in germinal center-derived lymphoma

“…20 Cell cycle analysis was determined by flow cytometry after staining with 50 μg/mL propidium iodide (Invitrogen). Cell proliferation rate was also determined, at the indicated times, by flow cytometry after staining with carboxyfluorescein succinimidyl ester (CFSE; Invitrogen).…”

“…16,17 Additionally the B-cell receptor, by stabilizing the amount and activity of the oncoprotein c-Myc, 18,19 might facilitate B-cell lymphomagenesis through the CD19/RAS/ERK pathway, which can promote the expression of anti-apoptotic proteins. 19,20 Indeed, previous experimental data acquired through the use of Eμ-Myc transgenic mice demonstrated that the c-Myc/ERK/CD19 feedback signaling loop is important for the malignant transformation of B cells and in determining the severity of lymphomas. 19,20 Chromosomal overexpression of translocation-elicited c-Myc induces the transcription of cyclin and cyclin-dependent kinase (CDK) genes which also relies significantly on CD19/ERK cascade-mediated phosphorylation of c-Myc on Ser62.…”

“…19,20 Indeed, previous experimental data acquired through the use of Eμ-Myc transgenic mice demonstrated that the c-Myc/ERK/CD19 feedback signaling loop is important for the malignant transformation of B cells and in determining the severity of lymphomas. 19,20 Chromosomal overexpression of translocation-elicited c-Myc induces the transcription of cyclin and cyclin-dependent kinase (CDK) genes which also relies significantly on CD19/ERK cascade-mediated phosphorylation of c-Myc on Ser62. 19 Specifically, CD19-mediated MYC/IGH translocation-induced (MYC/IGH+) B-cell lymphomagenesis can be inhibited by deleting the scaffold protein kinase suppressor of RAS-1 (KSR1) or treatment with MEK/ERK inhibitors.…”

“…19 Specifically, CD19-mediated MYC/IGH translocation-induced (MYC/IGH+) B-cell lymphomagenesis can be inhibited by deleting the scaffold protein kinase suppressor of RAS-1 (KSR1) or treatment with MEK/ERK inhibitors. 20 Nevertheless, it remains unclear whether CD19 expression itself contributes alone to the regulation of c-Myc protein stability and activity in GC lymphoma, or whether CD19 expression is directly regulated by c-Myc transcriptional activity. The characterization of these molecular mechanisms might provide novel insights into the biology of GC lymphoma and reveal prognostic factors and therapeutic targets.…”