Deletion of Pleiotrophin (PTN), a Vascular Niche Paracrine Factor, Abrogates Chronic Myeloid Leukemia Pathogenesis In Vivo

Tyrosine kinase inhibitor (TKI) therapy revolutionized the treatment of patients with chronic myeloid leukemia (CML), but TKI therapy alone is not curative.  Leukemic stem cells (LSCs) are considered to be resistant to TKI therapy in CML, although the mechanisms which confer LSC resistance to TKI-mediated eradication remain poorly understood.  Our laboratory has previously described the role of PTN, a paracrine factor which is secreted by bone marrow endothelial cells (BM ECs) and is necessary for the self-renewal and regeneration of normal hematopoietic stem cells (HSCs) in vivo.  We hypothesized that PTN signaling in the BM vascular niche might also be important in CML pathogenesis and perpetuation of LSCs.  In order to test our hypothesis, we crossed SCL-tTA/BCR-ABL mice, which develop CML over time under the control of doxycycline-treatment, with either PTN-/- or PTN+/+ mice, and compared CML pathogenesis in vivo.  SCLtTA/BCR-ABL;PTN+/+ mice displayed evolution of chronic phase CML (splenomegaly, increased WBCs, left-shifted myelopoiesis, decreased survival) within 90-120 days.  In contrast, SCLtTA/BCR-ABL;PTN-/- mice displayed normal range WBCs, decreased splenomegaly and significantly increased survival over the same time period.  At 300 days post-induction of BCR-ABL, 33% percent of SCLtTA/BCR-ABL;PTN-/- mice remain alive compared to only 7% of SCLtTA/BCR-ABL;PTN+/+ mice (p<0.0001).  Importantly, treatment of human CML cells with a specific anti-PTN antibody (BD Biosciences) significantly decreased CML colony formation in methylcellulose (P=0.02), whereas normal human CD34+ cells were unaffected.  This result suggested the novel possibility that human CML cells may produce PTN in an autocrine manner as a means to propagate disease.  These studies suggest that genetic or pharmacologic antagonism of PTN signaling is a potent strategy to inhibit CML pathogenesis.  Ongoing studies will determine if PTN-targeted therapy, with or without TKIs, can mediate the eradication of LSCs which are responsible for perpetuation of this disease.