HS1 has a central role in the trafficking and homing of leukemic B cells.
The function of the intracellular protein hematopoietic cell-specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1(-/-) mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2(-/-)γ(c)(-/-) mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone Eμ-TCL1 transgenic mice crossed with HS1-deficient mice were compared with Eμ-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL.
Unit of Lymphoid Malignancies, Division of Molecular Oncology, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
Cristina
C
Scielzo
Maria T S
MT
Bertilaccio
Giorgia
G
Simonetti
Antonis
A
Dagklis
Elisa
E
ten Hacken
Claudia
C
Fazi
Marta
M
Muzio
Valeria
V
Caiolfa
Daisuke
D
Kitamura
Umberto
U
Restuccia
Angela
A
Bachi
Martina
M
Rocchi
Maurilio
M
Ponzoni
Paolo
P
Ghia
Federico
F
Caligaris-Cappio
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000473:pathology*; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000473:pathology / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014407:Tumor Cells, Cultured
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; D004268:DNA-Binding Proteins; C061909:HCLS1 protein, human; C094983:Hcls1 protein, mouse