Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia
J. Clin. Invest. Iwona Konieczna, et al. 118:853 doi:10.1172/JCI33742 [Go to this article.]

Figure 6
ICSBP tyrosine phosphorylation regulated differentiation and HSC expansion. (A) Expression of the ICSBP transgene. ICSBP transgene expression in mice transplanted with WT or Y-mut ICSBP–expressing ICSBP^–/– bone marrow was determined by real-time PCR. Expression of these 2 transgenes was not significantly different at 20 weeks. WT transgene decreased significantly at 28 weeks (*P < 0.01). Wnt transgene expression was significantly less than Y-mut transgene expression (**P < 0.01). (B) Bone marrow CD34 expression. Bone marrow was analyzed by real-time PCR for CD34 expression. CD34 expression was not significantly different in control versus Y-mut ICSBP–expressing ICSBP^–/– bone marrow at 20 (*P < 0.001) or 28 (**P < 0.02) weeks but increased significantly over time (***P < 0.05). CD34 expression was significantly lower in mice transplanted with ICSBP-transduced ICSBP^–/– bone marrow (^#P < 0.02). (C) Bone marrow gp91^phox expression. Bone marrow gp91^phox expression was determined by real-time PCR. Expression was not significantly different in mice transplanted with control or Y-mut ICSBP–expressing ICSBP^–/– bone marrow (*P = 0.002). Expression was significantly greater at 20 weeks in mice transplanted with ICSBP-expressing ICSBP^–/– bone marrow (**P = 0.02) but decreased significantly by 28 weeks (***P < 0.01). (D) ICSBP deficiency impaired NADPH oxidase activity. Peripheral blood was obtained 16 weeks after transplantation and analyzed by NBT slide test. Results were expressed as percentage of NBT-positive PMNs (with or without PMA for oxidase activation). There were significantly more NBT-positive PMNs in mice transplanted with ICSBP^–/– bone marrow reexpressing ICSBP than with control or Y-mut ICSBP–expressing bone marrow (*P < 0.01). E76K SHP2 expression in WT (**P < 0.01) or ICSBP^+/– (***P < 0.01) bone marrow significantly decreased the percentage of NBT-positive PMNs.