The Bone Marrow Niche in Treatment-Resistant CML: A Review
Posted: Monday, November 18, 2019
According to a review by Helen Wheadon, BSc, PhD, and Caroline Busch, BSc, MSc, of the University of Glasgow, United Kingdom, published in Biochemical Society Transactions, preliminary research has shown that combined treatment with tyrosine kinase inhibitors (TKIs) and BMP receptor antagonists can target the deregulated bone morphogenetic protein (BMP) pathway in chronic myeloid leukemia (CML). Changes in the level of growth factors, such as BMPs, may signify a compromised bone marrow niche characteristic of treatment-resistant CML. Consequently, CML cells behaving like hematopoietic stem cells can “hijack” the bone marrow niche, leading to the persistence of therapy-resistant CML cells. The resulting low-level disease, attributable to BCR-ABL1–independent mechanisms, often necessitates lifelong TKI therapy for patients with CML.
In their review, the authors discussed how changes in levels of BMPs and proinflammatory cytokines can affect cell and extracellular matrix behavior, as well as bone remodeling in CML. Of note, high transcript levels of the BMPR1B/ALK6 receptor were detected in analyses of bone marrow samples from patients with chronic phase CML, but not in healthy controls. Molecular experiments had shown that increased surface expression of BMPR1B/ALK6 could be attributed to overexpression of BCR-ABL1. Moreover, compared with cells that have low levels of BMPR1B/ALK6, those with high levels better survived TKI treatment.
Promising strategies to target the deregulated BMP pathway in CML include the use of antibodies that target ligands such as BMP2, BMP4, BMP6, BMP7, and BMP10; antibodies that target receptors; or recombinant proteins of the BMP antagonists. However, the authors cautioned, “many current BMP receptor inhibitors display off-target effects and often inhibit more than one type of receptor…Future studies need to investigate not only combination therapy of TKIs and BMP antagonist[s], but also the physical cues and presentation of [growth factors] by the [extracellular matrix] in the [bone marrow] microenvironment.”
Disclosure: The study authors reported no conflicts of interest.