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

Abstract

Chronic myeloid leukaemia (CML) is a paradigm of precision medicine, being one of the first cancers to be treated with targeted therapy. This has revolutionised CML therapy and patient outcome, with high survival rates. However, this now means an ever-increasing number of patients are living with the disease on life-long tyrosine kinase inhibitor (TKI) therapy, with most patients anticipated to have near normal life expectancy. Unfortunately, in a significant number of patients, TKIs are not curative. This low-level disease persistence suggests that despite a molecularly targeted therapeutic approach, there are BCR-ABL1-independent mechanisms exploited to sustain the survival of a small cell population of leukaemic stem cells (LSCs). In CML, LSCs display many features akin to haemopoietic stem cells, namely quiescence, self-renewal and the ability to produce mature progeny, this all occurs through intrinsic and extrinsic signals within the specialised microenvironment of the bone marrow (BM) niche. One important avenue of investigation in CML is how the disease highjacks the BM, thereby remodelling this microenvironment to create a niche, which enables LSC persistence and resistance to TKI treatment. In this review, we explore how changes in growth factor levels, in particular, the bone morphogenetic proteins (BMPs) and pro-inflammatory cytokines, impact on cell behaviour, extracellular matrix deposition and bone remodelling in CML. We also discuss the challenges in targeting LSCs and the potential of dual targeting using combination therapies against BMP receptors and BCR-ABL1.

Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes

“…Evidence for this potentially occurring in AML, comes from findings showing that most of these factors are elevated in BM plasma and/or blood plasma of AML patients especially IL-6, CCL2, with a corresponding increase in M2-like CD206 + monocytes and M2-like CD163 + CD206 + Mφs ( Table 1 ) occurring in the BM of AML patients ( Mazur et al, 2007 ; Mussai et al, 2013 ; Sanchez-Correa et al, 2013 ; Su et al, 2013 ; Al-Matary et al, 2016 ). It is well-established that fibroblasts and MSCs also significantly contribute towards acquired BMME-driven therapy resistance in leukaemia and in particular AML ( Salman et al, 2015 ; Busch and Wheadon, 2019 ; Boutin et al, 2020 ). However, the impact of immunomodulation via BM infiltrating immune cells, such as monocytes and Mφs on drug resistance in AML, still remains largely unknown.…”

Targeting BMP signaling in the bone marrow microenvironment of myeloid leukemia

“…Indeed, BMP type-1 receptors inhibition has been shown to efficiently impact MIXL1-expressing AML cells (41). Collectively, these data support that targeting the BMP pathway could constitute a new therapeutic tool to decrease the progenitor capacity of LSCs (24,43).…”

<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

“…Alox12 Inhibition Disrupts NADH Homeostasis and Induces Oxidative Damage in CML Wnt/β-catenin, p53 and BMP pathways have been reported to play essential roles in maintaining BP-CML HSPC functions, including survival and self-renewal. [25][26][27] Although Alox12 inhibition negatively affected BP-CML HSPCs, Alox12 inhibition by ML355 did not affect transcriptional activities of Wnt/β-catenin, p53, and BMP as shown by luciferase reporter assays ( Figure 4A). In contrast, we found that Alox12 inhibition by both ML355 and siRNA knockdown significantly decreased levels of nicotinamide adenine dinucleotide phosphate (NADPH) and its reduced form NADH in K562 and BP-CML HSPCs ( Figure 4B and Figure S2A), suggesting that Alox12 inhibition disrupts NADH homeostasis.…”