Chronic myeloid leukemia stem cells require cell-autonomous pleiotrophin signaling
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
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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Research Article Hematology

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 6

Anti-PTN antibody suppresses human CML stem cell function.

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Anti-PTN antibody suppresses human CML stem cell function. (A) Human PTN...
(A) Human PTN levels in PB of healthy adults and patients with CML (n = 8–10/group). (B) Human PTN gene expression in BM CD34+ cells from healthy adults (n = 6) and CD34+ cells from patients with CML (n = 13). (C) ELISA of conditioned media from 72-hour cultures of BM cells from healthy adults and PB mononuclear cells from patients with CML (n = 8 wells/group from 3 samples/group). (D) Expression of PTP-ζ and ALK mRNA in BM CD34+ cells from healthy adults (n = 6) and CD34+ cells from patients with CML (n = 10). (E) Left: Representative histograms of PTP-ζ cell surface expression on CD34+ cells from healthy adults and patients with CML. Right: Percentage PTP-ζ+ cells (n = 5 healthy and n = 12 CML). (F) Left: CFCs from CD34+ cells treated in vitro with or without 50 μg/mL anti-PTN antibody (healthy donors, CML donors). Right: Fold differences in CFCs from CD34+ cell samples from healthy adults and patients with CML treated with anti-PTN or IgG (n = 5 donors/group). Fold changes are relative to the IgG control. (G) Left: Flow cytometric analysis of human CD45+ CML cells in NSG mice at 16 weeks after transplantation. Right: Mean human CD45+ cell engraftment at 16 weeks (n = 9–10 mice/group). (H) Left: Tumors from NSG mice at 2 weeks after injection of K562 cells cultured with or without IM for 72 hours. Mice were treated systemically with anti-PTN or IgG for 2 weeks. Right: Tumor masses are shown (n = 3–4 mice/group). P values were calculated using Mann-Whitney U test (A–E) or 2-tailed Student’s t test (F–H). *P < 0.05, **P < 0.01, ***P < 0.001.