Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia.
RhoH is a hematopoietic-specific, GTPase-deficient member of the Rho GTPase family that functions as a regulator of thymocyte development and T-cell receptor signaling by facilitating localization of zeta-chain-associated protein kinase 70 (ZAP70) to the immunological synapse. Here we investigated the function of RhoH in the B-cell lineage. B-cell receptor (BCR) signaling was intact in Rhoh(-/-) mice. Because RhoH interacts with ZAP70, which is a prognostic factor in B-cell chronic lymphocytic leukemia (CLL), we analyzed the mRNA levels of RhoH in primary human CLL cells and showed a 2.3-fold higher RhoH expression compared with normal B cells. RhoH expression in CLL positively correlated with the protein levels of ZAP70. Deletion of Rhoh in a murine model of CLL (Emu-TCL1(Tg) mice) significantly delayed the accumulation of CD5(+)IgM(+) leukemic cells in peripheral blood and the leukemic burden in the peritoneal cavity, bone marrow and spleen of Rhoh(-/-) mice compared with their Rhoh(+/+) counterparts. Phosphorylation of AKT and ERK in response to BCR stimulation was notably decreased in Emu-TCL1(Tg);Rhoh(-/-) splenocytes. These data suggest that RhoH has a function in the progression of CLL in a murine model and show RhoH expression is altered in human primary CLL samples.
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
A
A
Sanchez-Aguilera
I
I
Rattmann
D Z
DZ
Drew
L U W
LU
Müller
V
V
Summey
D M
DM
Lucas
J C
JC
Byrd
C M
CM
Croce
Y
Y
Gu
J A
JA
Cancelas
P
P
Johnston
T
T
Moritz
D A
DA
Williams
D000818:Animals; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D011947:Receptors, Antigen, B-Cell; C447841:RhoH protein, human; C496930:RhoH protein, mouse; D014157:Transcription Factors; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020741:rho GTP-Binding Proteins