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

Abstract

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.

Bone marrow niche crosses paths with BMPs: a road to protection and persistence in CML

“…Laperrousaz et al revealed deregulation of BMPR1B/ALK6 and downstream signalling elements, such as SMAD1, SMAD4, SMAD5, SMAD6, ID2 and RUNX1 in CP CML patients compared to healthy controls [103] . Deregulation of the pathway was also confirmed by Toofan et al who showed that differential expression of BMP pathway genes such as ACV1C, INHBA, SMAD7, SNAIL1 and SMURF2 could be linked to treatment response [105] . BMPR1B/ALK6 was identified as the main driver for myeloid progenitor expansion with BCR-ABL1 oncogene being sufficient to increase BMPR1B/ALK6 cell membrane expression in CML [103] .…”

“…Our results showed that dual targeting of BMP pathway signalling and BCR-ABL1 leads to altered cell cycle gene transcription, irreversible cell cycle arrest, along with increased apoptosis compared to single treatments. More importantly, inhibition resulted in fewer cell divisions, reduced numbers of CD34 + cells and colony formation from CML patient samples compared with healthy controls [105] . These promising results suggest that this approach warrants further investigations.…”

“…Recent studies indicate both an intrinsic and extrinsic deregulation of the BMP pathway in CML patients, with alterations most prevalent in TKI resistant patients [103][104][105], [106] . Laperrousaz et al revealed deregulation of BMPR1B/ALK6 and downstream signalling elements, such as SMAD1, SMAD4, SMAD5, SMAD6, ID2 and RUNX1 in CP CML patients compared to healthy controls [103] .…”

“…Deregulation of BMP signalling in CML upon TKI pressure needs to be further investigated in the future with the aim to identify key downstream target genes and to understand the crosstalk between BMP receptors, integrins and the ECM within the BM niche. Preliminary experiments have shown that combinatorial treatment of TKIs along with BMP receptor antagonists are a promising therapeutic approach to target the deregulated intrinsic and extrinsic BMP pathway in CML [105] . However, many current BMP receptor inhibitors display off target effects and often inhibit more than one type of receptor.…”

Acute Lymphoblastic Leukaemia Cells Impair Dendritic Cell and Macrophage Differentiation: Role of BMP4

“…The generation of immunosuppressive/tolerogenic DCs and M2 MØs has been proposed to be induced by different tumour-mediated mechanisms such as hypoxia, endoplasmic reticulum stress, and mainly exposition to several tumour-derived cytokines and growth factors [6,8,13,48]. In this context, the components of the TGF-β superfamily, including the BMPs, have been extensively reported to participate in multiple aspects of tumour biology including immune evasion [21,49,50,51] but the relevance of BMP pathway in the origin and progression of leukaemias and lymphomas is now beginning to be uncovered [24,52]. Our present data show that Nalm-6 ALL cells mainly secrete BMP4, but not other BMP ligands previously reported to be involved in lymphoid malignancies [24,53].…”