HIV-1 Rev–binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice
Shariq S. Khwaja, … , Jan van Deursen, Richard J. Bram
Shariq S. Khwaja, … , Jan van Deursen, Richard J. Bram
Published June 1, 2010
Citation Information: J Clin Invest. 2010;120(7):2537-2548. https://doi.org/10.1172/JCI41277.
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Research Article Hematology

HIV-1 Rev–binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice

Abstract

Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev–binding protein (Hrb), a component of the clathrin-mediated endocytosis machinery, as a critical mediator of Notch-induced T-ALL development in mice. Hrb was found to be a direct transcriptional target of Notch1, and Hrb loss reduced the incidence or delayed the onset of T-ALL in mouse models in which activated Notch1 signaling either contributes to or drives leukemogenesis. Consistent with this observation, Hrb supported survival and proliferation of hematopoietic and T cell precursor cells in vitro. We demonstrated that Hrb accelerated the uptake of transferrin, which was required for upregulation of the T cell protooncogene p21. Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis. Taken together, these results reveal that Hrb is a critical Notch target gene that mediates lymphoblast transformation and disease progression via its ability to satisfy the enhanced demands of transformed lymphoblasts for iron. Further, our data suggest that Hrb may be targeted to improve current treatment or design novel therapies for human T-ALL patients.

Authors

Shariq S. Khwaja, Hudan Liu, Caili Tong, Fang Jin, Warren S. Pear, Jan van Deursen, Richard J. Bram

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Figure 9

Iron is critical for T cell precursor development and for ICN1-induced leukemogenesis.

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Iron is critical for T cell precursor development and for ICN1-induced l...
(A) Hrb+/+ and Hrb–/– CD4–CD8– DN cells were seeded on OP9DL1 stromal beds. DFO was added at 0.5 and 5.0 μM 2 days after cells were plated. Total cell numbers were counted 2 days after treatment. Fold reduction in cell number was calculated in relationship to 0 μM DFO. (B) Lethally irradiated recipient mice received 25,000 ICN1-transduced BM cells. 7 mice were given normal feed, and 8 mice were given a low-iron diet immediately after transplant and were maintained on their respective diets. Additionally, 5 recipient mice that were transplanted with 25,000 MigR1-transduced BM cells were kept on the same low-iron diet as controls. Maintenance on a low-iron diet delayed death by ICN1-induced leukemogenesis (P = 0.0001 using log-rank Mantel-Cox test). (C) Model for the role of Hrb in oncogenic Notch signaling: Notch activation after loss of CBP or somatic mutation of Notch1 can lead to Hrb upregulation and cell transformation. Hrb upregulation is required for efficient transferrin uptake, resulting in increased intracellular iron for the transformed cell. This increase in iron uptake leads to increased p21 protein levels. Together, these molecular changes contribute to the survival and proliferation of the Notch-transformed cell, resulting in leukemia. Data are shown as mean ± SD. ***P < 0.001.