| First Author | Patrussi L | Year | 2019 |
| Journal | Haematologica | Volume | 104 |
| Issue | 10 | Pages | 2040-2052 |
| PubMed ID | 30819907 | Mgi Jnum | J:293864 |
| Mgi Id | MGI:6453798 | Doi | 10.3324/haematol.2018.209981 |
| Citation | Patrussi L, et al. (2019) p66Shc deficiency in the Emu-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape. Haematologica 104(10):2040-2052 |
| abstractText | The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the Emu-TCL1 mouse model of chronic lymphocytic leukemia. We showed that Emu-TCL1/p66Shc(-/-) mice developed an aggressive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in Emu-TCL1 mice. Emu-TCL1/p66Shc(-/-) mice displayed substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to correlate inversely with these cells' level of p66Shc expression. p66Shc expression declined with disease progression in Emu-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant therapeutic target. |
