Abstract
PTH-mediated modulation of the bone marrow microenvironment reduces CML but not AML growth.
Major finding: PTH-mediated modulation of the bone marrow microenvironment reduces CML but not AML growth.
Mechanism: Bone remodeling induced by PTH increases TGFβ1 signaling, which impairs CML LSC maintenance.
Impact: Treatment with PTH reduces CML LSCs and may eliminate human CML progenitors.
Activation of parathyroid hormone (PTH) receptor in the bone marrow stimulates bone remodeling and increased bone turnover and has been shown to regulate normal hematopoietic stem cell survival. However, it is unclear whether PTH signaling and modulation of the bone marrow microenvironment affect leukemic stem cells (LSC). Krause and colleagues found that osteoblast cell–specific overexpression of an activated form of the PTH receptor impaired the proliferation and maintenance of LSCs in the bone marrow niche and reduced disease progression in a mouse model of BCR–ABL1-driven chronic myelogenous leukemia (CML)-like myeloproliferative neoplasia (MPN). In contrast, PTH-induced bone remodeling accelerated the growth of acute myeloid leukemia (AML) driven by expression of the oncogene mixed-lineage leukemia (MLL)–MLLT3 (also known as AF9), suggesting that the LSC niche is distinct in CML and AML and that alteration of the bone marrow microenvironment may differentially regulate LSCs in these diseases. Consistent with this idea, bone marrow TGFβ1 signaling induced by PTH-stimulated bone remodeling selectively suppressed the growth of TGFβ receptor 1 (TGFBR1)-expressing CML progenitors but not AML cells. In addition, TGFBR1 depletion in BCR–ABL1+ cells enhanced CML-like MPN development, supporting a tumor-suppressive role for TGFβ1 in CML LSCs, and TGFBR1 expression in MLL–AF9+ AML cells prolonged survival in tumor-bearing mice. TGFβ1 increased downstream SMAD signaling in CML LSCs, whereas AML LSCs were insensitive to this effect. Furthermore, treatment with PTH reduced LSC frequency in wild-type mice and decreased LSC engraftment in immunodeficient mice transplanted with patient-derived CML cells. These results suggest that PTH-mediated modulation of the bone marrow microenvironment may represent a therapeutic strategy to specifically target and eliminate LSCs in patients with CML.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
RSS Feeds