Excessive proliferation and impaired function of primitive hematopoietic cells in bone marrow due to senescence post chemotherapy in a T cell acute lymphoblastic leukemia model

Abstract

Background: In clinic settings, rel apsed leukemic patients are found to be more fragile to chemotherapy due to delayed or incomplete hematopoietic recovery, and hematopoiesis of these patients seem to be impaired. Methods: We established a leukemia therapy model with a non-irradiated T cell acute lymphoblastic leukemia mouse model combined with cytarabine and cyclophosphamide. Dynamic kinetics and functional status of both primitive hematopoietic cells and leukemic cells in a leukemia host under the chemotherapy stress were comprehensively investigated. Results: We successfully established the leukemia therapy model with T lymphoblastic phenotype. After treatment with cytarabine and cyclophosphamide, the frequency of L-K+S+ hematopoietic cells tides with the therapy, and stabled when the disease remission, then reduced when relapsed, while leukemic cells showed a delayed but consistent regeneration. Combination of chemotherapy significantly promote an early and transient entrance of L-K+S+ hematopoietic cells into active proliferation and induction of apoptosis on L-K+S+ cells in vivo. Moreover, in the competitive bone marrow transplantation assays, hematopoietic cells showed gradually diminished regenerative capacity. Testing of senescence-associated beta-galactosidase (SA-β gal) status showed higher levels in L-K+S+ hematopoietic cells post therapy when compared with the control. Gene expression analysis of hematopoietic primitive cells revealed up-regulated p16, p21, and down-regulated egr1 and fos. Conclusion: We conclude that primitive hematopoietic cells in bone marrow enter proliferation earlier than leukemic cells after chemotherapy, and gradually lost their regenerative capacity partly by senescence due to accelerated cycling.