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P.M. Le et al.
highlighted complex tumor-host interactions within the BM during AML progression. Malignant cells compete with their normal counterparts for niche resources and occupancy, and disrupt normal hematopoiesis by inflict- ing a differentiation block, which often manifests itself as BM failure and pancytopenia.6,7 In these conditions, leukemic cells seem to lose sensitivity to antiproliferative cues from the niche.8 Under the expansion of leukemia, MSCs have shown signs of “reprogramming”.9-11 In partic- ular, the role of the osteoblast-rich region of the BM has been implicated in both AML chemoresistance and relapse.12,13 Unraveling the mechanisms underlying osteogenic niche-mediated support to AML cells is key to identifying molecular targets in order to develop effective drug therapies. In this review, we focus on advances in our understanding of the osteogenic niche in the leukemic BM microenvironment and discuss the key components of this niche as therapeutic candidates in AML.
Osteolineage cells regulate normal hematopoiesis
Non-random distribution of HSCs in the BM highlights the role of osteolineage cells in HSC maintenance. The physical association of HSCs with the endosteum corre- lates strongly with the colony formation and proliferative capacity of HSCs, and is primarily evident after BM trans- plantation.14,15 Anatomical evidence has provided the basis on which the functional relationships between oste- olineage cells and HSCs have continued to be unraveled. Osteoblasts secrete cytokines and growth factors includ- ing granulocyte-colony stimulating factor (G-CSF),16 hepatocyte growth factor,17 and osteopontin (OPN),18 which have been shown to maintain the pool size of the CD34+ progenitor population in the BM. Osteoblasts mediate HSC migration in and out of the BM, primarily through the CXCL12/CXCR419 and VCAM-1/VLA-420 axes, and under the influence of the sympathetic nervous system.21 In a knockout mouse model lacking bone mor- phogenetic protein (BMP) receptor I, Zhang et al.22 report- ed that an increase in HSC number was associated exclu- sively with a cell population that lined the long bone and had an osteoblastic phenotype. Similarly, Calvi et al.23 demonstrated that increasing osteoprogenitor or pre- osteoblast activation by augmenting parathyroid hor- mone (PTH) signaling enriched Lin- Sca-1+ c-Kit+, or HSC- like, cells in vivo. Interestingly, this HSC expansion occurred without substantially affecting the overall num- ber of hematopoietic cells. These observations suggest that PTH-induced signaling in osteoprogenitor cells or pre-osteoblasts might play a selective role in maintaining HSC self-renewal but not in the proliferation of their committed progenitors. How osteoblasts regulate HSC quiescence has been rigorously investigated. Loss of lig- and-receptor interactions, such as angiopoietin-1 receptor tyrosine kinase 2 (Ang-1/Tie2)24 and thrombopoietin-MPL (TPO/MPL),25 deregulates not only cell-cycle checkpoints but also coping mechanisms against extrinsic stressors, resulting in a reduction in slow-cycling hematopoietic cells. Stem-cell exhaustion and reduced self-renewal capacity after inhibition of Wingless (Wnt) signaling in osteoblasts further suggest that the mechanism underly- ing osteoblast-mediated regulation of HSCs does not fol- low a single axis.26
Surprisingly, osteoblast ablation, although associated with poorer HSC engraftment in vivo, does not lead to a massive loss of quiescent HSCs.27 It has also been shown
that osteoblast deficiency in chronic inflammatory condi- tions, such as rheumatoid arthritis, does not affect the fre- quency of Lin- Sca-1+ c-Kit+ cells or their long-term repop- ulating potential.28 Mice with conditional deletion of CXCL1229 or stem cell factor (SCF)30 in osteoblasts do not exhibit HSC defects. It is possible that osteoblastic regu- lation of HSCs overlaps with other regulatory pathways and hence is easily compensated. Different osteolineage members may also share common signals while differing in the degree of impact.31 Together, these data suggest that osteolineage cells or more primitive cells such as MSCs orchestrate a diverse, though possibly non-essen- tial, network of signals to maintain the stemness of HSCs and prompt hematopoietic activities, such as mobiliza- tion and expansion, in response to physiological needs.
Altered osteogenic niche leads to myeloid leukemia in BM
It has been firmly demonstrated that mutations affect- ing the ability of HSCs to differentiate into mature hematopoietic cells transform HSCs into pre-leukemic cells, and ultimately to leukemic cells when additional mutations are acquired (Figure 1).32-34 However, very little is known about the influence of other cellular compo- nents in the BM microenvironment on leukemic transfor- mation of hematopoietic cells.
The Scadden group was the first to show that genetic alterations in osteolineage cells could lead to myelodys- plastic syndromes (MDS) and leukemia. Deletion of Dicer1, a critical RNA processor and microRNA synthesiz- er, in Osterix (Osx)-expressing osteoprogenitor cells in a conditional knockout mouse model caused MDS and, on occasions, secondary AML.35 These mice first developed severe cytopenia and myelodysplasia, which transformed into monoblastic AML in 4 out of 200 cases, presenting as invasive myeloid sarcomas, anemia, and monocyte-like blast expansion in the peripheral blood, spleen, and BM. Of interest, Dicer1 was intact in the myeloblastic tumors, suggesting that dysfunctional osteoblast precusors could mediate clonal evolution in neoplastic formation. Similarly, constitutive activation of β-catenin in mouse osteoblasts resulted in a broad spectrum of dysfunctional hematopoiesis, including monocytosis, lymphocytope- nia, and somatic mutations that resembled those of human AML in myeloid progenitors. Kode et al.36 noted that both wild-type mice engrafted with long-term (LT) HSCs from β-catenin-mutant mice and β-catenin-mutant mice engrafted with healthy BM cells developed AML and died shortly after transplantation. These observations suggest that an altered osteogenic niche could induce per- manent damage to LT-HSCs and transform them to pre- leukemic and/or leukemic cells. Kousteni et al. attributed this niche-induced carcinogenesis to the oncogenic role of FoxO members involved in bone formation, which, sur- prisingly, are known tumor suppressors.37,38 This discov- ery sparks a debate about whether osteoblasts differen- tially regulate normal and malignant hematopoiesis. Recently, Dong et al.39 also reported that mice with a mutant allele of protein tyrosine phosphatase SHP2 (Ptpn11) in osteoprogenitors or Nestin+ MSCs could develop juvenile myelomonocytic leukemia-like myelo- proliferative neoplasms (MPN). With concomitant muta- tions in HSCs, mice with mutated MSCs were twice as likely to progress from MPN to acute leukemia as were mice with altered endothelial cells. This study under-
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haematologica | 2018; 103(12)