Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen

Abstract

BackgroundLeukemia is a systemic malignancy originated from hematopoietic cells. The extracellular environment has great impacts on the survival, proliferation and dissemination of leukemia cells. The spleen is an important organ for extramedullary hematopoiesis and a common infiltration site in lymphoid malignancies. Splenomegaly, frequently observed in T cell acute lymphoblastic leukemia (T-ALL), is associated with poor prognosis. However, how the spleen microenvironment distinctly affects T-ALL cells as opposed to bone marrow (BM) microenvironment has not been addressed.MethodsA Notch1-induced mouse T-ALL model was applied in this study. Flow cytometry and two-photon fluorescence microscopy were used to analyze early distribution of T-ALL cells. MILLIPLEX® MAP Multiplex Immunoassay was performed to measure cytokine/chemokine levels in different microenvironments. Transwell and co-culture experiments were used to test the effects of splenic microenvironment in vitro. Splenectomy was performed to assess the organ specific impact on the survival of T-ALL-bearing mice.ResultsMore leukemia cells were detected in the spleen than in the BM after injection of T-ALL cells by flow cytometry and two-photon fluorescence microscopy analysis. By screening a panel of cytokines/chemokines, a higher level of MIP-3β was found in the splenic microenvironment than BM microenvironment. In vitro transwell experiment further confirmed that MIP-3β recruits T-ALL cells which express a high level of MIP-3β receptor, CCR7. Furthermore, the splenic microenvironment stimulates T-ALL cells to express a higher level of MIP-3β, which further recruits T-ALL cells to the spleen. Co-culture experiment found that the splenic microenvironment more potently stimulated the proliferation and migration of T-ALL cells than BM. Moreover, the mice transplanted with T-ALL cells from the spleen had a shorter life span than those transplanted from BM, suggesting increased potency of the T-ALL cells induced by the splenic microenvironment. In addition, splenectomy prolonged the survival of leukemic mice.ConclusionsOur study demonstrates an organ specific effect on leukemia development. Specifically, T-ALL cells can be potentiated by splenic microenvironment and thus spleen may serve as a target organ for the treatment of some types of leukemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0071-7) contains supplementary material, which is available to authorized users.

Organ-Specific Microenvironment Modifies Diverse Functional and Phenotypic Characteristics of Leukemia-Associated Macrophages in Mouse T Cell Acute Lymphoblastic Leukemia

“…The development of leukemia in vivo is governed by numerous intrinsic and microenvironmental factors. We previously demon- strated that Notch1-induced T-ALL could be potentiated by microenvironmental cues in the spleen (46). We did not observe any significant splenomegaly in clodronate liposomes-treated mice, which indicated that LAMs had effects on the development of leukemia in vivo.…”

“…We reported previously that the spleen microenvironment stimulated the proliferation and dissemination of Notch1-induced leukemia cells more potently than did the BM microenvironment. MIP-3b, which was higher in the spleen microenvironment than in the BM microenvironment, accounted for the greater potential to recruit T-ALL cells (46). We observed that spleen LAMs stimulated the proliferation of T-ALL cells more strongly, which suggested that they might play an important role in the spleen microenvironment to promote the development of T-ALL.…”

Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation

“…In fact, the leukemic spleen was also able to promote leukemic cell homing and proliferation in comparison with leukemic BM. 33 In addition, the potentially increased inflammatory cytokines cannot explain the increased number of quiescent HSCs during leukemia development, despite the fact that previous reports have demonstrated an increased cycling fraction of HSCs under infection stress. 34,35 Our future studies will focus on (1) the extrinsic effects of leukemia on normal HSCs, including the alterations in cytokines and niche cells in leukemic BM, (2) how cytokine or niche cells regulate Egr3 expression in HSCs, and (3) the relationship between Egr3 and cell cycle regulatory genes.…”

Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow

“…We used a non-irradiated Notch1-induced mouse T-ALL model that was described previously 13,21 . C57BL/6J mice served as the control.…”