Hematology

ISSN: 1024-5332 (Print) 1607-8454 (Online) Journal homepage: http://www.tandfonline.com/loi/yhem20

Roles of the bone marrow niche in hematopoiesis,

leukemogenesis, and chemotherapy resistance in
acute myeloid leukemia

Andi Wang & Hua Zhong

To cite this article: Andi Wang & Hua Zhong (2018): Roles of the bone marrow niche in
hematopoiesis, leukemogenesis, and chemotherapy resistance in acute myeloid leukemia,
Hematology, DOI: 10.1080/10245332.2018.1486064

To link to this article: https://doi.org/10.1080/10245332.2018.1486064

Published online: 14 Jun 2018.

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HEMATOLOGY
https://doi.org/10.1080/10245332.2018.1486064

Roles of the bone marrow niche in hematopoiesis, leukemogenesis, and

chemotherapy resistance in acute myeloid leukemia
Andi Wang and Hua Zhong
Department of Hematology, South Campus Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic
of China

ABSTRACT KEYWORDS
Objectives: To summarize the effects of the bone marrow niche on hematopoiesis and Bone marrow niche;
leukemogenesis and discuss the chemotherapy resistance that can arise from interactions leukemogenesis; acute
between the niche and leukemia stem cells. myeloid leukemia;
Methods: We review the major roles of the bone marrow niche in cell proliferation, adhesion chemotherapy resistance
and drug resistance. The signaling pathways and major molecular participants in the niche
are discussed. We also address potential niche-targeting strategies for the treatment of acute
myeloid leukemia (AML).
Results: The bone marrow niche supports normal hematopoiesis and affects acute myeloid
leukemia (AML) initiation, progression and chemotherapy resistance.
Discussion: AML is a group of heterogeneous malignant diseases characterized by the
excessive proliferation of hematopoietic stem and/or progenitor cells. Even with
intensive chemotherapy regimens and stem cell transplantation, the overall survival rate
for AML is poor. The bone marrow niches of malignant cells are remodeled into a
leukemia-permissive environment, and these reformed niches protect AML cells from
chemotherapy-induced cell death. Inhibiting the cellular and molecular interactions
between the niche and leukemia cells is a promising direction for targeted therapies for
AML treatment.
Conclusions: Interactions between leukemia cells and the bone marrow niche influence
hematopoiesis, leukemogenesis, and chemotherapy resistance in AML and require
ongoing study. Understanding the mechanisms that underlie these interactions will help
identify rational niche-targeting therapies to improve treatment outcomes in AML
patients.

Introduction Bone marrow niche and its effects on

hematopoiesis and leukemogenesis
Acute myeloid leukemia (AML) is a malignant clonal
disease of hematopoietic stem and progenitor cells The bone marrow microenvironment, also known as
(HSPCs). Despite aggressive chemotherapy and stem the bone marrow niche, was first proposed by
cell transplantation, the prognosis for young patients Schofield in 1978 [8]. It contains the bone marrow
with AML remains unsatisfactory: the 5-year overall sur- mesenchymal stem and progenitor cells, osteolineage
vival rate is approximately 40%. The survival rate in cells, sinusoidal endothelium, perivascular stromal
adults more than 60 years old is also poor, and 60%– cells, adipocytes, unmyelinated Schwann cells,
80% of patients eventually die of refractory and/or immune cells (mainly regulating T cells), and many
relapsed leukemia. In older adults aged 65–70, the 5- other components, including a variety of adhesion
year survival rate is only 10% [1]. Residual leukemic factors, growth factors, and chemokines [9]. The
stem cells (LSCs) in the bone marrow niche are less sen- bone marrow niche influences the biological behavior
sitive to chemotherapy and are a major clinical factor in of hematopoietic stem cells (HSCs) via different sig-
disease relapse [2–4]. To prolong overall survival in naling cascades and maintains normal hematopoiesis.
patients with AML, new strategies other than epige- HSCs can be localized in the endosteal region adja-
netic modification and immunomodulation are cent to osteoblasts and in the vascular area, which
needed. Treatment strategies that attempt to eliminate is full of sinusoid endothelial cells (ECs) and perivas-
leukemia cells by focusing on the interaction between cular cells. As shown in Figure 1, these two zones
LSCs and the bone marrow niche might be useful clini- are defined as the endosteal and vascular niches,
cally [5–7]. respectively, and they act on HSCs synergistically to

CONTACT Hua Zhong zhh_lj@163.com Department of Hematology, South Campus Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong
University, 2000 Jiang Yue Road, Shanghai 201100, People’s Republic of China
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. WANG AND H. ZHONG

Figure 1. Bone marrow niche and associated cellular interactions. HSCs interact with and are regulated by an intricate and vibrant
multicellular bone marrow niche. They have close anatomical and functional relationships with cells in the bone marrow. The
players in the bone marrow niche include cytokines, the extracellular matrix, adhesion factors, and the sympathetic nervous
system. Osteolineage cells, immune cells, stromal cells, and neurons are collectively involved in several ligand–receptor interactions
such as CXCL12/CXCR4, VLA-4/VCAM-1, and the Ang-1/Tie2 axis, which orchestrate the colonization, differentiation, and homing of
HSCs. OB, osteoblast; CAR cell, CXCL12-abundant reticular cell; T-reg, regulatory T cell; Opn, osteopontin; G-CSF, granulocyte-colony
stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; CXCL12, CXC chemokine ligand 12; CXCR4, receptor
for CXCL12; VCAM-1, vascular cell adhesion molecule 1; VLA-4, very late antigen 4; Ang-1, Angiopoietin-1; IL, interleukin.

regulate cell self-renewal, proliferation and differen- established a mouse model that constitutively
tiation [9]. expressed Wnt inhibitory factor 1 (Wif1, a pan Wnt
The endosteal niche is composed of sinusoidal inhibitor) on a specific promoter region of osteoblasts.
endothelium, perivascular stromal cells, and osteoline- They found that the numbers of HSPCs in bone marrow
age cells (osteoblasts and osteoclasts) [3]. Osteoblasts, and the spleen increased sharply, along with an
cover the endosteum and form an interface between increase in the proportion of dividing HSPCs. The
the bone and the marrow. There are two types of bone morphogenetic protein (BMP) signal regulated
osteoblasts: spindle-shaped N-cadherin+ osteoblasts the HSC pool through the BMP receptor type IA
(SNO) and oval-shaped osteoblasts [10]. These cells (BMPRIA) [10]. Osteoblast-enriched ALCAM+Sca-1−
provide a haven for quiescent HSCs. The binding of cells, a subgroup isolated from CD45−CD31−Ter119−
HSCs with osteoblasts, especially SNO cells, maintains endosteal cells, significantly promoted the long-term
cell dormancy and is mediated by adhesion factors reconstitution activity of HSCs. The expression levels
involved in the Ang-1/Tie2 and TPO/MPL signaling of osteoblastic markers and relevant adhesion mol-
pathways [11,12]. Osteoblast ablation can provoke ecules such as Runt-related transcription factor 2
quiescent cells to enter the proliferating cycle [13]. (Runx2), CD44, VCAM-1, Cadherin 11, Cdh2, and
Osteoblasts also play a vital role in regulating HSC Alcam were also comparatively increased [18]. N-cad-
content [14]. Myriad studies have demonstrated the herin and β-catenin have been shown to be requisite
close relationship between osteoblasts and hemato- adhesion molecules that mediated the interaction
poiesis. Osteoblast-deficient transgenic mice exhibits between SNO cells and long-term HSCs [10]. Direct
reduced bone formation and a hematopoietic failure regulation of erythrocytes and an indirect effect on B
in bone marrow accompanied by enhanced extrame- lymphopoiesis by osteoblasts has also been demon-
dullary hematopoiesis [15]. A transgenic mouse strated [19,20]. However, osteoblasts can also nega-
model has been generated to produce osteoblast- tively affect the proliferation of HSCs. Increased bone
specific, activated PTH/PTHrP receptors (PPRs) under marrow cellularity and the higher proportion of
the control of the alpha-1 collagen promoter [16]. cycling hematopoietic progenitor cells in osteopon-
The osteoblastic cell count in the trabecular bone of tin-null (Opn−/−) mice compared to wild-type controls
the col1-caPPR mice was much higher than that of suggest that Opn has a suppressive effect on HSCs. The
the controls, leading to hematopoietic cell growth number of in vitro CD34+CD38− cells cultured with
through Notch activation. Schaniel et al. [17] thrombin-cleaved bovine Opn (tcOpn) decreased at
 HEMATOLOGY 3

the trend level [21]. In general, osteoblasts derived samples [30]. The ECs also support the proliferation of
from multipotent mesenchymal stromal cells (MSCs) leukemia blasts and are actively involved in leukemo-
sustain long-term HSC survival, proliferation, and quies- genesis. The co-culture of AML cells with microvascular
cence by secreting various cytokines, chemokines, and ECs resulted in the proliferation of malignant cells and
signaling molecules. exacerbated the AML phenotype. The co-culture also
The vascular niche, also known as the endothelial established a chemoprotective niche, characterized by
niche, comprises arterioles, capillaries, and fenestrated the high expression of soluble factors, including IL-3,
sinusoidal vessels. It mainly consists of vascular ECs, IL-6, stem cell factor (SCF), granulocyte-colony stimulat-
and CXCL12 abundant reticular cells (CAR cells), ing factor (G-CSF), and granulocyte macrophage-colony
which promote the differentiation and proliferation stimulating factor (GM-CSF). In a complementary study,
of short-term HSCs [22,23]. As soon as HSCs are mobi- the abnormal secretion of these angiocrine factors
lized, they leave the intima to reach the vascular area, potently inhibited the apoptosis of leukemia cells and
which is associated with hematopoietic reconstitution. promoted their growth via paracrine mechanisms [31].
The HSCs have an intimate relationship with ECs. However, inhibition of angiocrine receptors abrogated
Specialized ECs support HSC maintenance, differen- chemotherapy-induced angiogenesis and successfully
tiation, and self-renewal via multiple angiocrine reversed the resistance of AML [32].
factors and play an active role in regulating the Neural regulation also plays an important role in the
homing and trafficking of HSCs via the CXCR4/ development of myeloid malignancies. In a mouse
CXCL12 and RANK/RANKL pathways [24]. The CAR model, damaging the sympathetic nervous system
cells overexpress vascular cell adhesion molecule-1 increased the infiltration of leukemia, increased adre-
(VCAM-1), E-/P-selectin, CD44, interleukins (ILs), and nergic signaling transduced by Adrβ2-supported leuke-
platelet-derived growth factor (PDGF), all of which mogenesis and regulated the fate of LSCs [33].
have regulatory roles in cell adhesion and angiogen- Taken together, these studies suggest that hemato-
esis [25]. poietic cells and niche cells work synergistically in
Alterations of niche cells can contribute to disease healthy states and hematopoietic malignancies.
initiation or progression. For example, elevated
numbers of granulocyte/macrophage progenitors in
Role of the bone marrow niche in
the spleen, peripheral blood, and bone marrow have
chemotherapy resistance
been found in RARγ-deficient mice. When these bone
marrow progenitors were engrafted onto wild-type The bone marrow niche mediates cell resistance to
mice, the wild-type mice did not develop a myelopro- chemotherapy via small molecules secreted by osteo-
liferative-like disease. These results suggest that the blasts, ECs, and stromal cells and by direct cell-to-cell
myeloproliferative syndrome phenotype is at least par- contact mediated by adhesion factors. Accordingly,
tially caused by a defective bone marrow microenvir- drug resistance can be either soluble factor-mediated
onment, rather than by the mutation of drug resistance (SM-DR) or cell adhesion-mediated
hematopoietic cells [26]. Genetic alterations in niche drug resistance (CAM-DR). As noted above, soluble
cells may also contribute to hematopoietic disorders. molecules in the bone marrow niche include CXCL12,
The loss of the miRNA processing endonuclease VEGF, IL-6, FGF, G-CSF, and others. These molecules
Dicer1 from osteoprogenitors in a mouse model mediate chemotherapy resistance via different mech-
resulted in many myelodysplastic features, but trans- anisms. Vascular endothelial growth factor C (VEGF-C)
plantation of these hematopoietic cells into wild-type facilitates leukemia progression with a higher ratio of
mice did not result in any abnormalities [27]. The Bcl-2 to Bax, which suggests suppressive effects on
mutation of β-catenin in osteoblasts stimulated the cell apoptosis. It has also been shown to rescue leuke-
expression of Jagged-1, and the activation of the mia cells from chemotherapy-induced cell death [34].
Notch signaling pathway induced AML development The contribution of osteoblasts to chemotherapy
with chromosomal alterations [28]. resistance in AML includes aspects of both SM-DR
Similar to their healthy counterparts, malignant cells and CAM-DR. Osteoblasts have been shown to
reside in a complicated, self-strengthening leukemic protect AML cells from CXCL12-induced cell death
microenvironment. They alter the bone marrow niche through a soluble factor-mediated mechanism in
at the expense of normal hematopoiesis to facilitate both CXCL12-expressing AML cell lines, and clinical
their own growth and reinforce neoplastic disease pro- patient samples [35]. In addition, HSCs and leukemic
cesses. The endothelial niche can be hijacked by leuke- cells tightly adhere to osteoblasts on the bone
mia cells and it has been demonstrated that AML cells surface or stroma via a series of adhesion factors (integ-
integrate into the vascular endothelium by cell fusion rins and cadherins) and extracellular matrix proteins
or attachment and become dormant [29]. Increased (fibronectin and osteopontin). These cell-to-cell or
microvascular density and levels of angiogenesis have cell-to-matrix interactions play a critical role in the
been found in AML compared to normal bone marrow process of mobilization and homing and in drug
4 A. WANG AND H. ZHONG

resistance and clinical recurrence [3]. The bone marrow survival signaling pathways, including the MEK/ERK,
niche is a vital source of factors that facilitate the survi- JAK/STAT, and PI3K/AKT axes [40]. Rombouts et al.
val of malignant cells and enable the development of [41] found that CXCR4 levels in AML patients with an
minimal residual disease (MRD). Several signal trans- FMS-like tyrosine kinase-3/internal tandem duplication
duction pathways are highly associated with shielding (Flt3/ITD) mutation were markedly increased. A sub-
the bone marrow niche from malignant cells. Next, we sequent study demonstrated that CXCR4 might act as
discuss recent concepts concerning how these net- a useful indicator of an unfavorable prognosis even in
works impinge on leukemia cell proliferation, survival, AML with a normal karyotype [42]. The CXCL12/
and drug resistance (Figure 2). CXCR4 interaction is highly involved in cell survival,
adhesion, and migration [43,44]. CXCL12 is considered
a potent chemoattractant for both normal hemato-
Interaction between VLA-4 and VCAM-1 or
poietic cells and leukemic cells [45]. CXCR4 activation
fibronectin
has been shown to be a prerequisite for the migration
The adherence of AML cells to the bone marrow micro- of mobilized AML cells beneath marrow stromal cells
environment via VLA-4 leads to CAM-DR. VLA-4 is an [46]. As such, malignant cells tend to use CXCR4 to
integrin dimer, α4β1, which is located on leukemic access the protective niches that are usually restricted
cells. Fibronectin (FN) is a major component of the to normal HSCs and thereby reside in a safe haven
extracellular matrix and is secreted by various cells. that favors their survival and promotes resistance to
The VLA-4–FN interaction plays an instrumental role conventional chemotherapies. CXCR4-deficient mice
in chemokine-mediated homing and mobilization [36] showed aberrant B-lymphopoiesis, defective myelopoi-
and is closely related to MRD. Matsunaga et al. [37] esis [47], and restored sensitivity to the myelosuppres-
found that AML cells coated with FN had lower apopto- sive antimetabolite 5-fluorouracil (5-FU) [48].
sis rates and higher survival rates than those cultured Osteoblasts also had a protective effect on AML cells
with BSA in vitro. AML patients who are VLA-4 negative and induced cell cycle arrest in MV4–11 cell lines. The
have much higher overall survival rates than those with combination of G-CSF and AMD3100, a CXCR4
high VLA-4 expression. The negative prognostic value blocker, successfully inhibited cell adhesion and
of VLA-4 in AML might imply that physical contact migration, promoted cell division in AML and disrupted
between fibronectin and VLA-4-positive AML cells the interaction between the endosteal niche and leuke-
reduces chemotherapy sensitivity and provides a sanc- mia cells [49]. Sison et al. [50] demonstrated that the
tuary for MRD, ultimately resulting in a shorter survival upregulation of surface CXCR4 on AML cells was a poss-
time. With anti–VLA-4–specific antibodies, cells from ible mechanism of drug resistance, and AMD3100
VLA-4–positive AML patients co-cultured with stromal reversed the resistance and diminished stromal protec-
cells or FN tend to be more sensitive to chemotherapy tion. Inhibition of the CXCR4 pathway can disturb cell–
than those without VLA-4 antibodies. Poulos et al. [38] matrix communication and induce malignant cells to
have demonstrated that ECs establish a fertile niche, mobilize from the endosteal sanctuary. Such a pertur-
activation of ECs by VEGF-A leads to the expansion of bation might eventually overcome the protection of
AML cells and increases the number of EC-adherent leukemic cells by niche cells and sensitize them to che-
leukemia cells partly via VLA-4/VCAM-1 interaction. Fur- motherapeutic agents, ultimately decreasing the tumor
thermore, ECs stimulated by VEGF-A conferred che- burden. Another small-molecule reversible antagonist
motherapeutic protection on AML cells. In contrast, of CXCR4 is AMD3465, which also successfully abro-
the inhibition of VEGFR2 led to a profound increase gated protection against chemotherapy-induced cell
in chemosensitivity. apoptosis and enhanced the chemosensitivity of AML
cells both in vivo and in vitro [51,52]. These results
suggest a potential role for CXCR4-targeting molecules
CXCL12/CXCR4 pathway
in the treatment of AML.
For CAM-DR, the CXCL12/CXCR4 axis is indispensable.
Protected by the marrow stroma, residual leukemia
TPO/MPL signaling pathway
cells show little sensitivity to traditional chemotherapy.
This sensitivity is mainly mediated by the crosstalk The thrombopoietin (TPO) receptor, also known as
between CXCL12 (also known as stromal cell-derived myeloproliferative leukemia protein (MPL), was first
factor-1, SDF-1) and its receptor CXCR4. CXCL12 is identified from the myeloproliferative leukemia virus
widely expressed by CAR cells, osteoblasts, fibroblasts, (v-mpl). The TPO/MPL signaling pathway plays an
and ECs [39], and it usually binds with chemokine important role in many physiologic and pathologic pro-
receptor CXCR4, which belongs to a G-protein cesses. TPO, which is also secreted by osteoblasts, is the
coupled receptor. The binding of CXCL12 to CXCR4 ligand of MPL and has long been known to regulate the
can trigger the phosphorylation of CXCR4, promote process of megakaryopoiesis. TPO/MPL signaling is
calcium flux, and activate some downstream pro- vital for HSC hibernation and self-renewal. MPL+ AML
 HEMATOLOGY 5

Figure 2. Crosstalk between leukemia cells and niche cells associated with drug resistance. Niche cells can be hijacked during leu-
kemogenesis, and malignant cells depend upon the endosteal or stromal components in the microenvironment. The drug resist-
ance of leukemia cells arises from their direct physical contact with the stroma and is conferred by soluble factors. Cell–cell adhesion
and multiple cytokines or growth factors affect malignant cells, at least in part, by evoking diverse intracellular pro-survival cascades
and by increasing ABC transporter-mediated drug efflux. FN, fibronectin; ECM, extracellular matrix; ABC transporter, ATP-binding
cassette transporter; MRP1, multidrug resistance-associated protein 1.

cells exhibit clonogenic potential and are associated Ang-1/Tie-2 and associated molecules
with drug resistance [53]. Exogenous TPO maintains
The interaction between angiopoietin-1 (Ang-1) in
cell dormancy and promotes HSC proliferation [54].
osteoblasts and Tie-2 on HSCs also plays a pleiotropic
The neutralization of MPL significantly decreased the
role in cell adhesion, survival, and quiescence. Tie-2 is
total HSC cell count and the number of dormant
a unique receptor tyrosine kinase and can also be
HSCs in the endosteal niche, together with down-regu-
expressed by ECs and AML cells [56]. Tie-2 dysfunction
lation of cell-cycle-related genes such as p57kip2 and
might induce cancer development, metastasis and
Tie2. Exogenous TPO also caused S phase entry, and
drug resistance. In hematologic neoplasms, elevation
the expression levels of p57kip2 and Tie2 genes
of Ang-1 is related to higher disease risk and shorter
increased at the trend level [55]. TPO plays a prominent
survival time in AML or MDS patients. Once Ang-1
role in hematopoietic malignancies and regulates leu-
binds to ECs, Tie-2 is phosphorylated, which promotes
kemogenesis. The levels of TPO and c-MPL were
the activation of the phosphatidylinositol 3-kinase (PI3-
found to be notably increased in AML patients, and
K)/Akt signaling pathway, and the knockdown of Tie-2
increased expression of TPO secreted by BMSC-
leads to decreased viability of malignant cells [57]. Arai
derived osteoblasts from AML patients was also
et al. [11] found that Tie-2+ HSCs treated by exogenous
observed. After treatment with daunorubicin(DNR),
Ang-1 became flattened and tended to cling tightly to
the viability of an AML cell line HEL was the highest
the bone surface. Mice transplanted with Tie-2+ c-
when they were co-cultured with osteoblasts origi-
kit+Sca-1+Lin− (KSL)-side-population (SP) cells cultured
nated from AML patients, while HEL-single cultured
with SCF, TPO, and Ang-1 retained much higher levels
group showed the lowest survival rate [12]. These
of donor cells than cells not cultured with Ang-1. The
results suggest that upregulation of TPO leads to DNR
cells also showed an inhibitory effect on cell division,
resistance, although the underlying mechanisms still
thus maintaining self-renewal. Those SP cells can be
need to be clarified. The TPO/c-MPL pathway partici-
regarded as LSCs in the leukemic situation and may
pates in LSC stemness and cell dormancy, which can
help malignant cells evade antileukemic therapy.
partially explain why malignant cells seem to escape
Ang-1 was also found to promote cell cycle arrest in
chemotherapeutic cytotoxicity. This signaling
EVl1 high leukemia cells, via maintenance of the G0/
pathway could be a promising therapeutic target for
G1 phase through p18 upregulation [58]. Similar
refractory and relapsed leukemia, and associated
studies have also shown that the CDK inhibitors p57
inhibitors or specific antibodies might enhance che-
and p18 increased after HSCs were treated with Ang-
motherapy sensitivity in AML.
1, suggesting that Ang-1/Tie-2 signaling can be a
6 A. WANG AND H. ZHONG

potent cell cycle regulator [59]. Considering that drug overall survival in AML patients. In a reduced pO2
resistance largely depends on cell dormancy in the environment (6% O2), the overexpression of CXCR4
bone marrow niche, activation of the Ang-1/Tie-2 axis was detected in patient samples and in AML cell
could be a feature of AML chemotherapy resistance lines, and increasing the O2 concentration resulted in
and could contribute to adverse prognosis. decreased CXCR4 expression, alterations of lipid rafts
by the depletion of cholesterol content in the cellular
membrane, and increased shedding of CXCR4+ micro-
Akt pathway
particles [70]. Hypoxia regulates stem cell fates and
Akt, also known as protein kinase B (PKB), was initially plays an indirect but vital role in tumor progression,
discovered as the oncogene in the transforming retro- metastasis, and drug resistance in hematopoietic
virus AKT8 [60]. It is known to suppress cell apoptosis, malignancies [71].
regulate proliferation, and participate in cancer inva-
sion and metastasis. Akt activation promotes HSC pro-
Osteopontin
liferation and might induce myeloproliferative disease,
T-cell lymphoma, and leukemic transformation [61]. It Osteopontin (Opn) is an extracellular matrix glyco-
can also phosphorylate FOXO transcription factors, protein secreted by endosteal osteoblasts. It plays a
which promote the translocation of FOXO proteins key role in cell dormancy, invasion and the develop-
from the nucleus to the cytoplasm [62]. This interesting ment of MRD. Diverse receptors expressed on the cell
phenomenon is an important mechanism to protect surface can interact with Opn, including CD44 and
HSCs from noxious stresses, lower cell metabolism, various integrins, including α4β1, α5β1, α9β1, and
and maintain a quiescent state [63]. In AML, up-regu- others. The β3 integrins play a vital role in leukemogen-
lation of the Akt pathway might predict poor prognosis esis and the chemoresistance of AML [72]. Retrospec-
and shorter survival time by regulating the expression tive studies have found a correlation between high
of proteins associated with chemotherapy resistance, levels of Opn expression and poor prognosis in AML
such as multidrug resistance-associated protein 1 patients [73,74]. Overexpression of Opn b and c iso-
(MRP1) and the membrane ATP-binding cassette forms led to angiopoiesis, and these isoforms might
(ABC) transporter [64]. Intriguingly, Tamburini et al. prevent the cell apoptosis induced by conventional
[65] found that constitutive activation of the PI3K/Akt chemotherapy in AML [75]. A bone marrow niche
pathway led to a favorable outcome in de novo AML established an Opn-rich area can specifically recruit
patients. A possible mechanism for these outcomes is Opn-expressing blasts. In turn, leukemic cells secrete
that PI3K promotes entry of LSCs into the S phase, Opn into the niche. Opn regulation probably entails
thus improving susceptibility to chemotherapy. A positive feedback through host-tumor cell interactions.
more comprehensive understanding of the PI3K/Akt/ Opn can also expand the quiescent microenvironment
mTOR pathway should be sought. and endow leukemic blasts with resistance to che-
motherapy. A blockade of the Opn signaling pathway
markedly increased the proportion of cycling cells
Hypoxia and the HIF-1α pathway
and inhibited cell homing, which ultimately led to a
Oxygen in cells is unevenly distributed with levels higher tumor load. Injection of anti-Opn into engrafted
increasing on a gradient from the endosteum to sinu- mice followed by treatment with Ara-C decreased the
soids [66]. The levels of hypoxia-inducible factor 1α MRD burden compared with Ara-C chemotherapy
(HIF-1α), considered a marker of hypoxia, show the alone. The Opn neutralizer-treated mice might be vul-
opposite pattern. The role of hypoxia and HIF-1α in nerable to cytotoxic stresses [76].
hematologic malignancies remains controversial. In The bone marrow microenvironment can support
some studies, leukemogenesis acceleration and cell survival, differentiation, and proliferation. It can
enhancement of an even more aggressive MPN pheno- also maintain cell dormancy and mediate drug resist-
type was observed in transgenic mice with a Hif-1α del- ance via various signal transduction pathways, such
etion [67,68]. In contrast, hypoxia also induced cell as the interplay between VLA-4 and VCAM-1, the
cycle arrest and weakened the chemotherapy sensi- SDF-1/CXCR4 axis, and the TPO/c-MPL pathway. Many
tivity of AML cells, which might have been regulated adhesion molecules, soluble factors and cell com-
by a downstream-activated PI3K/Akt pathway and ponents in the bone marrow niche are interconnected
some antiapoptotic proteins [69]. Activation of the and ultimately form a sophisticated network.
hypoxia/HIF-1α pathway also facilitated angiogenesis
and enhanced cytokine secretion, both of which
Drug resistance mediated by leukemic stem
might induce chemotherapy resistance. Oxygen con-
cells
centration is considered a determinant parameter in
the regulation of the function and expression of We cannot ignore the role of LSCs in the bone
CXCR4, which correlates with drug resistance and marrow microenvironment and the pathogenesis of
 HEMATOLOGY 7

myeloid malignancies. LSCs share certain properties and ameliorated the stroma-mediated cytoprotection
with HSCs, including strong self-renewal capacities against spontaneous apoptosis. In in vivo systems
and multilineage differentiation. They can escape that mimic the physiologic microenvironment,
from apoptosis due to the remodeling of osteo- AMD3465 promoted cell mobilization and enhanced
blasts. Dormant LSCs are believed to underlie antitumor effects, contributing to a reduced AML
disease relapse and chemotherapy resistance in disease burden. Recently, the combination of plerixafor
AML [77]. By interacting with hematopoietic bone (AMD3100) with mitoxantrone, etoposide and AraC
marrow niches, LSCs maintain their quiescence and (MEC) was used in 52 AML patients. It achieved a rela-
self-renewal capacity. They can tolerate many cell tively satisfactory complete remission (CR) rate of 39%
cycle specific cytotoxic agents. Saito demonstrated compared with 21% for the MEC regimen
that pretreatment with G-CSF dramatically reduced (NCT00512252). The main pharmacological mechanism
the number of CD34+CD38− LSCs in the G0 phase disrupted the CXCR4/CXCL12 interaction and blocked
and was accompanied by an increase in actively downstream signals such as the PI3K/AKT and MAPK
dividing LSCs, which induced cell apoptosis and pathways. The mobilization rate of leukemic blasts
enhanced chemotherapy sensitivity. This finding also doubled without leukostasis, which may benefit
suggests new possibilities for AML treatment [78]. patients with refractory or relapsed AML by augment-
Relapse after chemotherapy is also characterized ing chemosensitivity [80]. Another Phase 2a trial (NCT
by more heterogeneous and complicated LSC popu- 01838395) focused on the CXCR4 antagonist BL-8040
lations [79]. (BKT140) and found an effect on the mobilization of
AML blasts. When BL-8040 was combined with Ara-C
in patients with relapsed or refractory AML, the differ-
Therapeutic targeting of the bone marrow
entiation of granulocytes increased, and the CR rates
niche
improved significantly [81]. Other CXCR4 antagonists
Enhancing the sensitivity of AML cells to chemother- and antibodies, including LY2510924, CX-01,
apy continues to be an active area of clinical POL6326, and NOX-A12, also potently hampered cell
research. In addition to novel cytotoxic chemother- growth and produced a sustained pharmacodynamic
apy agents, epigenetic modifiers of transcription effect on mobilization [82–85]. These trial results indi-
and cell cycle regulation are increasingly the focus cate that blockade of the CXCR4/CXCL12 axis could
of research. As knowledge about LSCs and the be used to supplement conventional chemotherapy.
bone marrow microenvironment has progressed, Other studies examining evolving targets that might
the protective effect of bone marrow stromal cells help to restore chemotherapy sensitivity in AML are
on leukemia cells and how these cells and microen- ongoing. Fogler et al. [86] first reported that a dual
vironments regulate chemotaxis, adhesion, and CXCR4/E-selectin inhibitor, GMI-1359, significantly pro-
homing have been increasingly well understood. moted mobilization in a mouse model of FLT3-ITD+
Addressing the combined effect of chemotherapy AML. The dual inhibitor functioned better than an
and specific drugs targeting bone marrow niches antagonist aimed at E-selectin or CXCR4 alone, and is
on leukemia cells can be a potential therapeutic considered an innovative drug to prolong survival of
direction to diminish MRD. FLT3-mutated AML. GMI-1271 is a specific E-selectin
The first preclinical trial focusing on the CXCL12/ antagonist that targets interactions between the
CXCR4 axis was conducted in 2009. It was designed bone marrow niche and cancer cells. Its safety,
to block the interactions of leukemic cells with niche efficacy, and pharmacokinetics in AML with a combi-
cells using the CXCR4 inhibitor AMD3465 to overcome nation of MEC or idarubicin and cytarabine (DA 7 + 3;
resistance to chemotherapy in AML [51]. AMD3465 suc- cytarabine for 7 days and idarubicin for 3 days)
cessfully inhibited the migration of primary AML cells regimen have been studied (NCT 02306291) [87]. In

Table 1. Summary of drugs that target the bone marrow niche in AML.
Drug Target/Role ClinicalTrial.gov Identifier Phase Reference
AMD3100/Plerixafor CXCR4 inhibitor NCT00512252 I/II [80,92]
BL-8040/BKT140 CXCR4 antagonist NCT03154827, NCT01838395 Ib/II, II [81,93]
Y2510924 CXCR4 antagonist NCT02652871 I [82]
CX-01 CXCR4 antagonist NCT02873338 II [83]
POL6326 CXCR4 antagonist NCT01413568 I/II [84]
BMS-936564/MDX-1338/Ulocuplumab Anti-CXCR4 antibody NCT01120457, NCT02305563 I,I/II [85]
GMI-1359 CXCR4/E-selectin antagonist Preclinical [86]
GMI-1271 E-selectin antagonist NCT 02306291 I/II [87]
FNIII14 VLA-4 antagonist Preclinical [88]
AS101 VLA-4 inhibitor NCT01010373 II [89]
Hu5F9-G4 Anti-CD47 antibody NCT03248479 Ib [90]
TH-302/Evofosfamide Hypoxia-activated prodrug NCT01149915 I [91]
8 A. WANG AND H. ZHONG

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