Internal tandem duplication mutations in FLT3 gene augment chemotaxis to Cxcl12 protein by blocking the down-regulation of the Rho-associated kinase via the Cxcl12/Cxcr4 signaling axis.

Internal tandem duplication mutations in the Flt3 gene (ITD-FLT3) enhance cell migration toward the chemokine Cxcl12, which is highly expressed in the therapy-protective bone marrow niche, providing a potential mechanism underlying the poor prognosis of ITD-FLT3(+) acute myeloid leukemia. We aimed to investigate the mechanisms linking ITD-FLT3 to increased cell migration toward Cxcl12. Classification of the expression of Cxcl12-regulated genes in ITD-FLT3(+) cells demonstrated that the enhanced migration of ITD-FLT3(+) cells toward Cxcl12 was associated with the differential expression of genes downstream of Cxcl12/Cxcr4, which are functionally distinct from those expressed in ITD-FLT3(-) cells but are independent of the Cxcr4 expression levels.