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 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

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 5

PTN promotes CML stem cell survival via induction of c-Jun and the UPR.

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PTN promotes CML stem cell survival via induction of c-Jun and the UPR. ...
(A) Jun, Atf4, and Xbp1 expression in splenic KSL cells at 12 weeks after BCR/ABL induction (dotted line = expression in KSL cells from NL C57BL/6 mice. (B) Left: Histograms of p-PERK in BM KSL cells from BA;PTN+/+ mice and BA;PTN–/– mice at 12 weeks after BCR/ABL induction, compared with C57BL/6 controls. Right: Percentage p-PERK+ cells within the KSL population (n = 5/group). (C) Jun, Atf4, and Xbp1 expression in KSL cells from control C57BL/6 mice and from BA;PTN+/+ mice treated with 100 ng/mL PTN in vitro (n = 4/group). (D) Fold change in Jun, Atf4, and Xbp1 mRNA expression at 2 hours following treatment with 10 μM anisomycin in KSL cells isolated from control C57BL/6 mice and BA mice (dotted line = baseline expression of each gene prior to anisomycin treatment). (E) Leukemic colonies from K562 cells following 72-hour incubation with Jun, Atf4, or Xbp1 siRNA or sham siRNA ± PTN (n = 5/group). (F) Annexin V analysis of splenic KSL cells from BA mice treated for 24 hours with IM with or without PTN (n = 5/group). (G) Leukemic colonies (CFCs) from splenic KSL cells from BA mice treated ± PTN with or without IM (n = 5/group, 2-tailed Student’s t test). (H) Jun, Atf4, and PTN expression in splenic KSL cells from BA mice in response to IM (n = 5–6/group; Ptn: *P < 0.05; Atf4: †P < 0.05; Jun: #P < 0.05). (I) Annexin V analysis of K562 cells treated with IM alone or IM with PTN, with and without the c-Jun peptide inhibitor or GSK2606414 (GSK, n = 3–6/group). P values were calculated using 2-tailed t test (A, D, and G), Dunnett’s multiple-comparisons test for 2-way ANOVA (C and E), or Dunnett’s multiple-comparisons test for 1-way ANOVA (B, F, H, and I). *P < 0.05, ***P < 0.001.