Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling
Heather A. Himburg, … , Gary Schiller, John P. Chute
Heather A. Himburg, … , Gary Schiller, John P. Chute
Published January 2, 2020; First published October 15, 2019
Citation Information: J Clin Invest. 2020;130(1):315-328. https://doi.org/10.1172/JCI129061.
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Research Article Hematology Stem cells

Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling

Abstract

Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell–specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.

Authors

Heather A. Himburg, Martina Roos, Tiancheng Fang, Yurun Zhang, Christina M. Termini, Lauren Schlussel, Mindy Kim, Amara Pang, Jenny Kan, Liman Zhao, Hyung Suh, Joshua P. Sasine, Gopal Sapparapu, Peter M. Bowers, Gary Schiller, John P. Chute

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Figure 2

PTN deletion impairs CML stem cell repopulating capacity.

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PTN deletion impairs CML stem cell repopulating capacity. (A) Experiment...
(A) Experimental design. (B) Donor CD45.2+ cell engraftment in PB of recipient mice transplanted with splenic KSL cells from BA;PTN+/+ mice or BA;PTN–/– mice (n = 7–10 mice/time point). (C) PB WBCs and neutrophils in the recipient mice at 10 weeks after transplant, along with controls (n = 5–10/group). (D) Left: Representative images of spleens from recipient mice transplanted with KSL cells from BA;PTN+/+ or BA;PTN–/– mice at 10 weeks after transplant, along with controls. Right: Mean spleen masses for each group (n = 6–10/group). (E) BCR/ABL transcript levels in the spleens of recipient mice (n = 7–9 per group). (F) Left: Representative flow cytometric analysis of donor myeloid (Mac1/Gr1+) cell engraftment in the BM of recipient mice. Right: Percentage BM total CD45.2+ cell and donor myeloid cell engraftment in each group (n = 7–10/group). (G) BCR/ABL transcript levels in the BM of recipient mice (n = 7–9 per group). P values were calculated using Sidak’s multiple-comparisons test for 2-way ANOVA (B) or 2-tailed Student’s t test (C–G). *P < 0.05, ***P < 0.001.