Chemoresistance and TRAIL-sensitivity in translocation 17;19-positive acute lymphoblastic leukemia

<p>Translocation 17;19 is a rare type of translocation in childhood acute lymphoblastic leukemia (ALL), and the prognosis of t(17;19)-positive ALL is extremely poor. Both primary samples and cell lines showed a significant resistance to vincristine and cytarabine in vitro. Indeed, high levels of minimal residual disease are commonly observed after remission induction therapy, and early relapses are frequently confirmed during or after early consolidation therapy with low-dose cytarabine. Besides the TCF3::HLF fusion gene, the TCF4::HLF and TCF3::TEF fusion genes are also identified in childhood ALL. The anti-apoptotic activity of TCF3::HLF itself is directly associated with a poor prognosis. Additionally, the overexpression of P-glycoprotein and mutations in the RAS pathway genes are background factors for poor prognosis. Of note, hypercalcemia is developed at diagnosis in approximately 40% of cases. Accompanying osteolytic bone lesions may disrupt the hematopoietic environment and result in a delayed recovery of normal hematopoiesis after chemotherapy, which is another background for refractoriness. In the graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation, donor-derived cytotoxic T cells induce cell death of the targeted leukemia cells via cytotoxic factors, including TRAIL. In t(17;19)-positive ALL, TCF3::HLF upregulates gene expression levels of the death receptors for TRAIL; as a result, leukemia cells are highly sensitive to the anti-leukemic activities of TRAIL. Furthermore, TRAIL mediates the anti-leukemic activities of blinatumomab and CAR-T cell therapy. Recently, the prognosis of patients with t(17;19)-positive ALL has been improving due to allogeneic hematopoietic stem cell transplantation after control of the residual disease using blinatumomab or CAR-T cell therapy.</p>