Page 148 - 2019_10 resto del Mondo_web

L. Patrussi et al.
Expression of CXCR4, which mainly guides B-cell homing to the bone marrow,26 was comparable in leukemic cells from both mouse strains (Figure 5A), accounting at least in part for the comparable extent of tumoral cell infiltra- tion in the spleen. Conversely, surface expression of CCR7, the main lymph node B-cell homing receptor,27 was higher in Eμ-TCL1/p66Shc-/- cells (Figure 5B). Expression of S1PR1, which controls B-cell egress from
A
secondary lymphoid organs,28 was strongly downregulat- ed in Eμ-TCL1/p66Shc-/- compared to Eμ-TCL1 cells (Figure 5C), in agreement with the causal relationship between p66Shc and S1PR1 expression in CLL cells.8 Consistent with these results and the massive lymph node colonization (Figure 4A), leukemic Eμ-TCL1/p66Shc-/- cell chemotaxis towards the CCR7 ligand MIP-3β and the S1PR1 ligand S1P was enhanced and suppressed, respec-
B
CD
E
Figure 2. p66Shc deficiency accel- erates leukemogenesis in Eμ-TCL1 mice. (A, B) Flow cytometric analy- sis of the percentages (A) and white blood cell (WBC) counts (B) of CD5+CD19+ cells in peripheral blood samples from either Eμ-TCL1 (n=87) or Eμ-TCL1/p66Shc-/- (n=134) mice collected at the indi- cated months. (C) Trend-lines calcu- lated on the monthly average per- centages of CD5+CD19+ cells in the Eμ-TCL1 and Eμ-TCL1/p66Shc-/- mice shown in (A). (D) Analysis of the percentages of sick mice, calcu- lated as the percentage of mice with ≥10% CD5+CD19+ cells, calcu- lated on the percentages of CD5+CD19+ cells shown in (A). (E) Log-rank survival analysis of the Eμ- TCL1 or Eμ-TCL1/p66Shc-/- mice shown in (A). Mean ± standard devi- ation. Mann-Whitney rank sum test. ****P≤0.0001; ***P≤0.001; **P≤0.01; ns: not significant.
2044
haematologica | 2019; 104(10)