Bone marrow microenvironment: The guardian of leukemia stem cells

Table 1 Possible molecules and their role in chronic myeloid leukemia stem cells-bone marrow microenvironment interaction

Target	Source	Role	Ref.
G-CSF	CML LSC	Mobilization	[15]
CD26	CML LSC	Mobilization	[16]
β1-integrins	CML LSC	Homing	[19]
Selectins	CML LSC, endothelial cells	Homing	[20]
CD44	CML LSC	Homing	[20]
Chemokines (MIP-1α, MIP-1β, etc)	BMM, CML LSC	Growth of CML LSC	[15,25]
Cytokines (IL-1α, IL-1β, TNFα, etc)	BMM, CML LSC	Growth of CML LSC	[15,25]
BMP2/4	MSC, CML LSC	Drug resistance	[26]
FGF2	MSC	Drug resistance	[28]
PIGF	MSC	Proliferation, metabolism	[29]
miR-126	CML LSC, endothelial cells	Dormancy	[30]
HIF-1	CML LSC	Growth of CML LSC	[15]
Jagged-1	Osteoblast	Dormancy	[94]
Parathyroid hormone	BMM	CML LSC removal	[95]
WNT	BMM	Growth of CML LSC	[21]
N-cadherin	CML LSC	Drug resistance	[21]

CML LSC: chronic myeloid leukemia stem cell; BMM: bone marrow microenvironment; MSC: mesenchymal stromal cell; G-CSF: granulocyte-colony stimulating factor; MIP-1α: macrophage inflammatory protein 1 alpha; MIP-1β: macrophage inflammatory protein 1 beta; IL-1α: Interleukin-1 alpha; IL-1β: Interleukin-1 beta; TNFα: tumor necrosis factor alpha; BMP2/4: bone morphogenetic protein 2/4; FGF2: fibroblast growth factor 2; PIGF: placental growth factor; HIF-1: hypoxia-inducible factor1.

Table 2 Possible molecules and their role in acute myeloid leukemia stem cells-bone marrow microenvironment interaction

Target	Source	Role	Ref.
VLA-4	AML LSCs	Homing	[37]
CD44	AML LSCs	Homing	[38,96]
CXCR4	AML LSCs	Adhesion	[40]
Jagged-1	Osteoblast	Proliferation	[42]
CXCR2	AML LSCs	Proliferation, survival	[44]
Parathyroid hormone	BMM	OB proliferation, LSCs growth	[97]
Proangiogenesis factors (VEGF, HGF, BFGF, VEGFR)	AML LSCs, BMM	Endothelial and LSC proliferation	[47,48]
Cytokines (IL-6, IL1β, TNFα, G-CSF, GM-CSF)	AML LSCs, BMM	Angiogenesis, LSC proliferation	[51]
Tie-2	Osteoblast	LSCs quiescent	[46]
CD36	AML LSCs	Energy source provider	[56]

AML LSC: Acute myeloid leukemia stem cell; BMM: Bone marrow microenvironment; VLA-4: Very late antigen-4; CXCR4: C-X-C chemokine receptor type 4; CXCR2: C-X-C chemokine receptor type 2; VEGF: Vascular endothelial growth factor; HGF: Hepatocyte growth factor; BFGF: Basic fibroblast growth factor; VEGFR: Vascular endothelial growth factor receptor; IL-6: Interleukin-6; IL-1β: Interleukin-1 beta, TNFα: Tumor necrosis factor alpha; G-CSF: Granulocyte-colony stimulating factor; GM-CSF: Granulocyte-monocyte colony stimulating factor.

Table 3 Chronic myeloid leukemia and acute myeloid leukemia stem cell markers for detection and selective targeting

Target	CD	CML LSC	AML LSC	Normal HSC	Normal progenitor	Ref.
IL-2Rα	CD25	+	+	-	+/-	[59,69]
DPP4	CD26	+	-	-	-	[16]
Siglec-3	CD33	+	+	+	+	[98]
SCARB3	CD36	+	+	+/-	+	[99]
Pgp-1	CD44	+	+	+	+	[38]
IAP	CD47	+	+	+	+	[70]
Campath-1	CD52	+	+	+	+	[100]
C1qR1	CD93	+	+	+/-	+/-	[101]
Tactile	CD96	-	+	-	-	[66]
MIC2	CD99	-	+	+	+	[102]
SCFR	CD117	+	+	+/-	+/-	[64]
IL-3Rα	CD123	+	+	+/-	+/-	[68]
CLL-1	-	+/-	+	+/-	+	[67]
TIM-3	-	-	+	+/-	+/-	[71]
IL-1RAP	-	+	+	-	+	[60,103]

CML LSC: Chronic myeloid leukemia stem cells; AML LSC: Acute myeloid leukemia stem cell; HSC: Hematopoietic stem cell; IL-2Rα: Interleukin-2 receptor alpha; DPP4: Dipeptidyl peptidase 4; Siglec-3: Sialic acid-binding immunoglobulin-type lectin-3; SCARB3: Mast/stem cell growth factor receptor; IL-3Rα: Interleukin receptor subunit α; CLL-1: C-type lectin-like molecule-1; TIM-3: T-cell immunoglobulin mucin-3; IL-1RAP: Interleukin-1 receptor accessory protein.

Table 4 A draft of compounds under clinical trial in leukemic stem cell bone marrow microenvironment target therapy

Disease	Target	Compound	Clinical trial ID
CML	CXCR4	BL-8040	NCT02115672
CML	IL-1RAP	CAR-LMC	NCT02842320
CML	JAK-inhibitor	Ruxolitinib	NCT01702064, NCT03654768, NCT01751425, NCT03610971
AML	CXCR4	Plerixafor (AMD3100)	NCT01455025
AML	Hypoxia	TH-302	NCT01149915
AML	VEGF	Aflibercept	NCT00601991
AML	VLA-4	AS101	NCT01010373
AML	Ang-1/2	Trebananib (AMG 386)	NCT01555268
AML	CD47	SRF231, TTI-621, CC90002, Hu5F9-G4	NCT03512340, NCT02663518, NCT02367196, NCT02678338, NCT03248479
AML	Notch	LY3039478, MK0752	NCT01695005, NCT00100152
AML	XIAP	AEG35156	NCT00363974
AML	BH3	ABT-199	NCT01994837
AML	Pan FGFR	LY274455	NCT01212107

CML: Chronic myeloid leukemia; AML: Acute myeloid leukemia; CXCR4: C-X-C chemokine receptor type 4; IL-1RAP: Interleukin-1 receptor accessory protein; JAK: Janus kinase; VEGF: Vascular endothelial growth factor; VLA-4: Very late antigen-4; Ang-1/2: angiopoietin-1/2; XIAP: X-Linked inhibitor of apoptosis; FGFR: Fibroblast growth factor receptor.