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

The fusion gene of ABL1 is closely related to tumor proliferation, invasion, and migration. It has been reported recently that ABL1 itself is required for T-cell acute lymphoblastic leukemia (T-ALL) cell migration induced by CXCL12. Further experiments revealed that ABL1 inhibitor Nilotinib inhibited leukemia cell migration induced by CXCL12, indicating the possible application of Nilotinib in T-ALL leukemia treatment. However, the interacting proteins of ABL1 and the specific mechanisms of their involvement in this process need further investigation. In the present study, ABL1 interacting proteins were characterized and their roles in the process of leukemia cell migration induced by CXCL12 were investigated. Co-immunoprecipitation in combination with mass spectrometry analysis identified 333 proteins that interact with ABL1, including Cofilin1. Gene ontology analysis revealed that many of them were enriched in the intracellular organelle or cytoplasm, including nucleic acid binding components, transfectors, or co-transfectors. Kyoto Encyclopedia of Genes and Genomes analysis showed that the top three enriched pathways were translation, glycan biosynthesis, and metabolism, together with human diseases. ABL1 and Cofilin1 were in the same complex. Cofilin1 binds the SH3 domain of ABL1 directly; however, ABL1 is not required for the phosphorylation of Cofilin1. Molecular docking analysis shows that ABL1 interacts with Cofilin1 mainly through hydrogen bonds and ionic interaction between amino acid residues. The mobility of leukemic cells was significantly decreased by Cofilin1 siRNA. These results demonstrate that Cofilin1 is a novel ABL1 binding partner. Furthermore, Cofilin1 participates in the migration of leukemia cells induced by CXCL12. These data indicate that ABL1 and Cofilin1 are possible targets for T-ALL treatment.

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

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.