Immature CML cells implement a BMP autocrine loop to escape TKI treatment

Grockowiak, Élodie; Laperrousaz, Bastien; Jeanpierre, Sandrine; Voeltzel, Thibault; Guyot, Boris; Gobert, Stéphanie; Nicolini, Franck E.; Maguer-Satta, Véronique

doi:10.1182/blood-2017-08-801019

Cited by 34 publications

(40 citation statements)

References 52 publications

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“…In the spleen of BMPR1a cKO mice, T cells were decreased while B cell increased. Tyrosine kinase inhibitor resistant CML patients exhibit higher BMP4 production and its receptor BMPR1b to form a CML promoting autocrine loop (42). Genetically inhibiting myeloid BMP signaling reduces tumor progression in our mouse model, confirming the requirement of BMPs in certain cancer contexts.…”

Section: Discussionsupporting

confidence: 73%

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

et al. 2020

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The Bone Morphogenetic Protein (BMP) pathway is a member of the TGFβ signaling family and has complex roles in cancer. BMP signaling is rarely mutated and can be frequently overexpressed in many human cancers. The dichotomous role of BMPs as both tumor promoters and suppressors appears to be largely context based in both the cancer cell and the surrounding microenvironment. Myeloid cells including macrophages and neutrophils have been shown to be tumor promoting when stimulated from BMPs. We found that conditional deletion of BMPR1a in myeloid cells (LysMCre) restricts tumor progression in a syngeneic mouse prostate cancer model. Specific changes occurred in myeloid cells both in tumor bearing mice and tumor naïve mice throughout multiple tissues. We profiled myeloid subsets in the bone marrow, spleen and primary tumor and found myeloid BMPR1a loss altered the differentiation and lineage capability of distinct populations by histologic, flow cytometry and high dimensional mass cytometry analysis. We further confirmed the requirement for BMP signaling with pharmacologic inhibition of THP-1 and Raw264.7 activated into M2 macrophages with the BMP inhibitor DMH1. M2 polarized primary bone marrow derived cells from LysMCre BMPR1a knockout mice indicated a distinct requirement for BMP signaling in myeloid cells during M2 activation. These results indicate a unique necessity for BMP signaling in myeloid cells during tumor progression.

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Section: Discussionsupporting

confidence: 73%

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

et al. 2020

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“…Interestingly, unlike the chronic phase of CML, in which we identified BMP2 and BMPR1B as driving the deregulation of the BMP pathway and SC/progenitor maintenance and expansion 12 , in AML BM cells, BMP4 and BMPR1A alterations were already detected at diagnosis. Interestingly, with CML progression towards more advanced phases and the acquisition of resistance to treatment, the BMP4 signal becomes predominant 38 . This suggests that the BMP4 signal is related to more aggressive or advanced disease as identified in cancers of other origins such as liver (HCC) 39 , thyroid (PTC) 40 and bladder 41 .…”

Section: Discussionmentioning

confidence: 99%

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Voeltzel¹,

Flores-Violante²,

Zylbersztejn³

et al. 2018

Cell Death Dis

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In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.

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“…However, ACVR1B (ALK4), BMPR1B (ALK6), ACVRIC (ALK7), ACVR2A , SMAD5 SMAD6, RUNX1 and RUNX2 showed the same expression pattern in both populations. Using the 18-month follow-up data, patients were stratified into optimal, warning and treatment failure categories (termed “good/intermediate/poor TKI responders”) according to the European LeukemiaNet 2013 TKI response criteria 19 . We tracked gene expression patterns to clinical response, to identify a gene signature for TKI-responders vs non-responders (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibiting type 1 BMP receptors with small-molecule inhibitors, in combination with TKIs, is a promising approach to deplete primitive CML stem/progenitor cells, especially given the emerging role of BMP pathway signalling in treatment resistance and disease relapse 16 , 19 . We demonstrate that combination treatment caused irreversible cell cycle arrest, increased apoptosis, reduced cell division and survival of CD34 + cells in CML compared to normal cells, with CML-iPSCs displaying less self-renewing potential and enhanced differentiation following therapy.…”

Section: Discussionmentioning

confidence: 99%

Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal

Toofan

Busch

Morrison³

et al. 2018

Cell Death Dis

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Leukaemic stem cell (LSC) persistence remains a major obstacle to curing chronic myeloid leukaemia (CML). The bone morphogenic protein (BMP) pathway is deregulated in CML, with altered expression and response to the BMP ligands shown to impact on LSC expansion and behaviour. In this study, we determined whether alterations in the BMP pathway gene signature had any predictive value for therapeutic response by profiling 60 CML samples at diagnosis from the UK SPIRIT2 trial and correlating the data to treatment response using the 18-month follow-up data. There was significant deregulation of several genes involved in the BMP pathway with ACV1C, INHBA, SMAD7, SNAIL1 and SMURF2 showing differential expression in relation to response. Therapeutic targeting of CML cells using BMP receptor inhibitors, in combination with tyrosine kinase inhibitor (TKI), indicate a synergistic mode of action. Furthermore, dual treatment resulted in altered cell cycle gene transcription and irreversible cell cycle arrest, along with increased apoptosis compared to single agents. Targeting CML CD34+ cells with BMP receptor inhibitors resulted in fewer cell divisions, reduced numbers of CD34+ cells and colony formation when compared to normal donor CD34+ cells, both in the presence and absence of BMP4. In an induced pluripotent stem cell (iPSC) model generated from CD34+ hematopoietic cells, we demonstrate altered cell cycle profiles and dynamics of ALK expression in CML-iPSCs in the presence and absence of BMP4 stimulation, when compared to normal iPSC. Moreover, dual targeting with TKI and BMP inhibitor prevented the self-renewal of CML-iPSC and increased meso-endodermal differentiation. These findings indicate that transformed stem cells may be more reliant on BMP signalling than normal stem cells. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to target LSC self-renewal and improve long-term outcome for patients.

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Immature CML cells implement a BMP autocrine loop to escape TKI treatment

Cited by 34 publications

References 52 publications

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

Loss of Myeloid BMPR1a Alters Differentiation and Reduces Mouse Prostate Cancer Growth

A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

Chronic myeloid leukaemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal

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