Rho GDP-Dissociation Inhibitor 2 Inhibits C-X-C Chemokine Receptor Type 4-Mediated Acute Lymphoblastic Leukemia Cell Migration

Abstract

Although we currently have a good understanding of the role C-X-C chemokine receptor type 4 (CXCR4) plays in T cell acute lymphoblastic leukemia (T-ALL), the mechanism of CXCR4-mediated T-ALL migration remains elusive. Therefore, we focus on the downstream signals of CXCR4 that contribute to T-ALL cell migration in this study. Rho GDP-dissociation inhibitor 2 (RhoGDI2) is expressed preferentially in lymphocytes. It interacts with and regulates the activation of Rho proteins by inhibiting the dissociation of GDP and the binding of GTP. In a previous study, we demonstrated that RhoA and RhoC are activated and required for CXCR4-mediated JURKAT cell migration. In the present work, we investigate the role of RhoGDI2 in CXCR4-mediated T-ALL cell migration. Results show that RhoGDI2 sh2 significantly releases its inhibition effects on T-ALL cell migration toward CXCL12 (C-X-C motif chemokine ligand 12). Phosphorylation of RhoGDI2 on Y24 and Y153 releases RhoA and RhoC from RhoGDI2, which recovers CXCR4-mediated migration toward CXCL12 although the phosphorylation of Y130 has less effect on RhoA or RhoC binding. Furthermore, Src is activated by CXCL12. Transfection of siRNAs to Src reduces CXCR4-mediated migration. Src is required for the phosphorylation of RhoGDI2 on Y153, and ABL1 is activated by CXCL12 and responsible for the phosphorylation of RhoGDI2 on Y24 and Y130. Similarly, knockdown of the expression of ABL1 by siRNAs reduces the CXCR4-mediated migration. Therefore, RhoGDI2 may be a brake for CXCR4-positive T-ALL migration. Because migration is a prerequisite for infiltration of leukemia, this work may suggest the possible involvement of RhoGDI2 in infiltration of T-ALL.

ABL1 and Cofilin1 promote T-cell acute lymphoblastic leukemia cell migration

“…In the studies of leukemia, researchers have paid more attention to the role of ABL1 transformation in causing leukemia and ignored the role of ABL1 itself. Our recent work shows that siRNA to ABL1 inhibited T-ALL migration towards CXCL12 [19]. The present study shows that the ABL1-specific inhibitor Nilotinib significantly reduced the migration of Jurkat and L1210 cells toward CXCL12 in vitro and infiltration into spleen in vivo (Figure 1).…”

“…ABL1 regulates Vav1, activation, and further affects Rac1/PAK1/LIMK1/cofilin signaling pathway [45]. In our previously published papers, ABL1-activated RhoA and RhoC have been shown to play a key regulatory role in CXCR4-mediated T-ALL cell migration [19,46]. In the present study, it was demonstrated that ABL1 is responsible for the migration of Jurkat and L1210 cells (Figure 1).…”

Diallyl disulfide downregulating RhoGDI2 induces differentiation and inhibit invasion via the Rac1/Pak1/LIMK1 pathway in human leukemia HL‐60 cells

“…It is common that members of the Rho GTPase family are strongly expressed in oncology investigations 30 . Several surveys have suggested that the first requirement for leukemic infiltration is migration, and that RhoGDI2 is probably a promoter for the development of metastasis in CXCR4‐positive T‐ALL that is also implicated in T‐ALL inflammation 31 . At the moment, studies on the actions, targets of action and specific physiological features of RhoGDI2 in the system of hematopoietic lymphocytes are not enough and require wider and more intensive investigations.…”

The Dual Function of RhoGDI2 in Immunity and Cancer

“…Additionally, phosphorylation of RhoGDI2 on Y24 or Y153 reduce its affinity for RhoA or RhoC, leading to their increased activity. Further investigations showed that the phosphorylation of RhoGDI2 was due to non-receptor protein tyrosine kinases Src and ABL1 in response to CXCR4 stimulation by CXCL12 in T-ALL [ 24 , 53 , 76 , 94 ].…”