Targeting BMP signaling in the bone marrow microenvironment of myeloid leukemia

Abstract

The bone morphogenetic protein (BMP) pathway regulates the fate and proliferation of normal hematopoietic stem cells (HSC) as well as interactions with their niche. While BMP2 and BMP4 promote HSC differentiation, only BMP4 maintains HSC pool and favors interactions with their niche. In myeloid leukemia, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in Chronic Myeloid Leukemia (CML) and Acute Myeloid leukemia (AML) responsible for leukemic stem cells (LSC) survival. In AML, BMP pathway alterations sustain and promote resistant immature-like leukemic cells by activating a new signaling cascade. Binding of BMP4 to BMPR1A leads to ΔNp73 expression, which in turn induces NANOG, altogether associated with a poor patient's prognosis. Despite efficient targeted therapies, like Tyrosine Kinase Inhibitors (TKI) in CML, many patients retain LSCs. Our laboratory demonstrated that the BMP pathway sustains a permanent pool of LSCs expressing high levels of BMPR1B receptor, that evolve upon treatment to progressively implement a BMP4 autocrine loop, leading to TKI-resistant cells. Single cell RNA-Seq analysis of TKI-persisting LSCs showed a co-enrichment of BMP with Jak2-signaling, quiescence and stem cell (SC) signatures. Using a new model of persisting LSCs, we recently demonstrated that BMPR1B+ cells display co-activated Smad1/5/8 and Stat3 pathways and could be targeted by blocking BMPR1B/Jak2 signal. Lastly, a specific BMPR1B inhibitor impaired BMP4-mediated LSC protection against TKIs. Altogether, data based on various studies including ours, indicate that BMP targeting could eliminate leukemic cells within a protective bone marrow microenvironment to efficiently impact residual resistance or persistence of LSCs in myeloid leukemia.

Altered BMP2/4 Signaling in Stem Cells and Their Niche: Different Cancers but Similar Mechanisms, the Example of Myeloid Leukemia and Breast Cancer

“…Indeed, inhibition of BMP signaling leads to CSC death, and interrupts BMP production by surrounding stromal cells, in cooperation with other current treatments which remain inefficient as monotherapies (Jeanpierre et al, 2021). This proof-of-concept established in the hematopoietic system is likely to be extended to other cancers (Jung et al, 2019;Lefort and Maguer-Satta, 2020). Collectively, data imply a major role for the BMP pathway in orchestrating the dynamics of the CSC niche ecosystem in different cancers and at all stages of tumor progression.…”

The Tyrosine Kinase-Driven Networks of Novel Long Non-coding RNAs and Their Molecular Targets in Myeloproliferative Neoplasms

“…In addition to intrinsic regulation, extrinsic regulation of the bone marrow microenvironment plays an important role in CML progression ( Kumar et al, 2020 ; Lefort and Maguer-Satta, 2020 ). Based on the findings of circulating lncRNAs, including H19 expression, we targeted the exosome compartment to investigate the potential regulatory role of LNC000093.…”

High-throughput measurements of bone morphogenetic protein/bone morphogenetic protein receptor interactions using biolayer interferometry

“…One study examined their role in chondrocyte proliferation and found that the deletion of BMP-2 gene alone resulted in severe chondrodysplasia while the deletion of BMP-4 led to a minor cartilage phenotype. 54 Likewise, in acute myeloid leukemia, a distinct role of BMP-4 versus BMP-2 has been evidenced: 55,56 BMP-4 solely is involved as it activates a specific signaling pathway promoting immature resistant leukemic cells, which eventually leads to a relapse after treatment. 55,56 In view of our findings regarding the specific differences between BMP-2 and BMP-4, it will be interesting to further evaluate their specific functions in different cell signaling contexts.…”