Figure 2
Figure 2. IGF1R inhibition is more efficient in CLL patient cells with a poor prognosis, and IGF1R engagement activates the PI3K and Erk pathways and its inhibition is associated with enhanced cell death and impaired downstream signaling. (A) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with a single dose of 15 µM AG1024, 1 µM PPP, or 1 µM linsitinib for 24 hours, and cell survival was determined by flow cytometry. Results are shown as mean ± SEM (n = 20). (B) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with a single dose of 15 µM AG1024 (AG) or 1 µM linsitinib (L) and immunoblotted for the expression of phosphorylated IGF1R and IRS-1 (n = 6). (C) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with a single dose of 1 µM PPP and were immunoblotted for the expression of phosphorylated IGF1R and IRS-1 (n = 4). (D) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with 5 to 15 µM AG1024 and underwent western blot analysis using the indicated antibodies. Results are represented as mean ± SEM (n = 10). Supplemental Figure 1C shows the associated densitometric analysis after treatment with 15 µM AG1024. (E) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with 10 to 500 nM rhIGF-1 and were immunoblotted for the expression of IGF1R, pIGF1R, pAkt, Akt, pERK, and Erk. A representative example from 4 independent experiments is shown. (F) CLL B cells from different patients were stratified according to different genetic aberrations and were compared for their responsiveness toward the IGF1R inhibitors AG1024 or PPP. Results are represented relative to DMSO-treated controls (n = 10). (G) CLL B cells from different patients were stratified according to distinct prognostic CLL subgroups and were compared for their responsiveness toward the IGF1R inhibitors AG1024 or PPP (mean ± SEM, n = 10). (H) CLL B cells with different mutational statuses were compared in their responsiveness toward the IGF1R inhibitors AG1024 or PPP (n = 10).

IGF1R inhibition is more efficient in CLL patient cells with a poor prognosis, and IGF1R engagement activates the PI3K and Erk pathways and its inhibition is associated with enhanced cell death and impaired downstream signaling. (A) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with a single dose of 15 µM AG1024, 1 µM PPP, or 1 µM linsitinib for 24 hours, and cell survival was determined by flow cytometry. Results are shown as mean ± SEM (n = 20). (B) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with a single dose of 15 µM AG1024 (AG) or 1 µM linsitinib (L) and immunoblotted for the expression of phosphorylated IGF1R and IRS-1 (n = 6). (C) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with a single dose of 1 µM PPP and were immunoblotted for the expression of phosphorylated IGF1R and IRS-1 (n = 4). (D) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with 5 to 15 µM AG1024 and underwent western blot analysis using the indicated antibodies. Results are represented as mean ± SEM (n = 10). Supplemental Figure 1C shows the associated densitometric analysis after treatment with 15 µM AG1024. (E) CLL B cells purified from freshly isolated or freeze-thawed PBMCs from CLL patient samples were treated with 10 to 500 nM rhIGF-1 and were immunoblotted for the expression of IGF1R, pIGF1R, pAkt, Akt, pERK, and Erk. A representative example from 4 independent experiments is shown. (F) CLL B cells from different patients were stratified according to different genetic aberrations and were compared for their responsiveness toward the IGF1R inhibitors AG1024 or PPP. Results are represented relative to DMSO-treated controls (n = 10). (G) CLL B cells from different patients were stratified according to distinct prognostic CLL subgroups and were compared for their responsiveness toward the IGF1R inhibitors AG1024 or PPP (mean ± SEM, n = 10). (H) CLL B cells with different mutational statuses were compared in their responsiveness toward the IGF1R inhibitors AG1024 or PPP (n = 10).

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