WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which was shown to correlate with ETV6-RUNX1 translocation and favorable prognosis in childhood leukemia. It has a broad expression pattern in hematopoietic and non-hematopoietic cells. Our previous work described WBP1L as a regulator of CXCR4 signaling and hematopoiesis. Here, we show that hematopoiesis in the mice with Wbp1l germline deletion is dysregulated, already at the level of hematopoietic stem cells and early progenitors. We further demonstrate that thymi of WBP1L-deficient mice are significantly enlarged and contain increased numbers of thymocytes of all subsets. This can potentially be explained by increased generation of multipotent progenitors 4 (MPP4) in the bone marrow, from which the thymus-seeding progenitors are derived. We also observed increases in multiple cell types in the blood. In addition, we show that WBP1L regulates hematopoietic stem cell functionality and leukocyte progenitor proliferation and gene expression during hematopoietic stem and progenitor cell transplantation, which contribute to more efficient engraftment of WBP1L-deficient cells. WBP1L thus emerges as a regulator of hematopoietic stem and progenitor cell function, which controls leukocyte numbers at the steady state and after bone marrow transplantation.

• Klíčová slova
• T cell development, WBP1L, hematopoiesis, hematopoietic stem and progenitor cell transplantation, hematopoietic stem cells, transmembrane adaptor protein,
• MeSH
• hematopoetické kmenové buňky * fyziologie   MeSH
• hematopoéza * MeSH
• membránové proteiny * genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• počet leukocytů MeSH
• regulace genové exprese MeSH
• thymocyty fyziologie   MeSH
• thymus * cytologie   fyziologie   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové proteiny * MeSH
• Wbp1l protein, mouse MeSH Prohlížeč

WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6-RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non-haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4-family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l-deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis.

• Klíčová slova
• CXCR4, ETV6, NEDD4 family, OPAL1, RUNX1, WBP1L, bone marrow homing, bone marrow transplantation, haematopoiesis, haematopoietic stem cell,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• glykoproteiny metabolismus   MeSH
• HEK293 buňky MeSH
• hematopoetické kmenové buňky metabolismus   MeSH
• hematopoéza * MeSH
• homeostáza MeSH
• lidé MeSH
• lipoylace MeSH
• malá interferující RNA metabolismus   MeSH
• membránové proteiny genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• receptory CXCR4 metabolismus   MeSH
• signální transdukce * MeSH
• ubikvitinace MeSH
• ubikvitinligasy metabolismus   MeSH
• vazba proteinů MeSH
• zárodečné buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• glykoproteiny MeSH
• malá interferující RNA MeSH
• membránové proteiny MeSH
• receptory CXCR4 MeSH
• ubikvitinligasy MeSH
• WBP1L protein, human MeSH Prohlížeč
• Wbp1l protein, mouse MeSH Prohlížeč