Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities

Table 1 Markers of leukemia stem cells

Cell surfacemarkers	Patient samples used	Mouse model used	Ref.
CD34+CD38-	FAB M1, M4, M5	NOD/SCID	[15,16]
CD34+CD38+	CN-AML, MLL-ENL	NOD/SCID + IVIG or anti-CD122	[18,64,67,68]
CD34-CD38+	AML with NPM1 mutation	NOD/SCID β-2 microglobulin NOD/SCID IL2 receptor γ−/− + IVIG	[66]
CD34+CD123+	FAB M1, M2, M4	NOD/SCID	[69]
CD34+CD38-CD96+	CK-AML, CBFB-MYH11, PML-RARA, AML1-ETO, FAB M4	Rag2-/- IL2RG-/-	[70]
CD34+CLL1+	AMLs with FLT3-ITD	NOD/SCID	[71]
TIM3+	FAB M1, M2, M4	NOD/Rag1-/- IL2RG-/-	[72]
CD34+CD38- CD33+CD13+	CN-AML, CBF-AML, MLL-ENL	NOD/SCID	[73]

FAB: French-American-British classification system; CN: Cytogenetically normal; CK: Cytogenetically complex; MLL-ENL: Mixed-lineage leukemia-eleven nineteen leukemia; NPM1: Nucleophosmin 1; CBFB-MYH11: Core binding factor beta unit-Myosin heavy chain 11; PML-RARA: Promyelocytic leukemia-retinoic acid receptor alpha; AML1-ETO: Acute myeloid leukemia 1 protein- eight twenty one; FLT3-ITD: Fms-like tyrosine kinase 3 Internal tandem duplication; NOD/SCID: Non-obese diabetic/severe combined immunodeficiency; Rag: Recombination activating gene; IL2RG: Interleukin 2 receptor subunit gamma.

Table 2 Emerging therapy targeting leukemia stem cells

Drug	Mechanism	Selected clinical trials	Phase	Ref.
Therapy targeting cell surface markers
GO	Anti-CD33 monoclonal antibody conjugated with calicheamicin, a potent antitumor anthracycline antibiotic	NCT00882102 NCT01869803 NCT00968071 NCT01409161 NCT00766116 NCT02724163 NCT00658814 NCT02473146 NCT00895934 NCT00006265 NCT00860639 NCT00927498 NCT00085709 NCT00195000 NCT00893399 NCT00017589	Phase I-III	[124,126, 130,132,133]
Hu5F9-G4	Anti-CD47 monoclonal antibody	NCT02678338	Phase I	[74,141]
CSL360	Anti-CD123 monoclonal antibody	NCT00401739	Phase I	[69,134]
DT388IL3/ SL-401	Anti-CD123 recombinant immunotoxin created by the fusion of diphtheria toxin with a ligand targeting the IL-3 receptor	NCT02113982 NCT00397579	Phase I-II	[69,134,136]
MGD006/ S80880	Anti-CD3 and CD123 DART	NCT02152956	Phase I	[137]
H90	Anti-CD44 monoclonal antibody	N/A	N/A	[75,139]
A3D8	anti-CD44 monoclonal antibody	N/A	N/A	[139]
Therapy targeting LSC-specific molecular pathways
Bortezomib	Proteasome inhibitor inhibits the degradation of the IkBa creating an anti-NF-κB effect	NCT00789256 NCT00382954 NCT01127009 NCT00666588 NCT00703300 NCT01534260 NCT00383474	Phase I-III	[36,143-147, 175-177]
Parthenolide	Inhibitor of NF-κB	N/A	N/A	[149]
Celastrol	Inhibitor of Hsp90 and by extension NF-κB	N/A	N/A	[150]
4-hydroxy- 2-nonenal	Product of lipid peroxidation, inhibiting the proteasome and NF-κB function	N/A	N/A	[151,152]
BKM120 CAL-101	PI3K inhibitors	NCT01396499 NCT01833169 NCT00710528	Phase I-II	[38,153,154]
GSK21110183 MK-2206 Perifosine	AKT inhibitors	NCT00881946 NCT01253447 NCT01231919 NCT00301938	Phase I-II	[38,155-157]
Sirolimus, everolimus, temsirolimus	mTOR inhibitors	NCT01184898 NCT01611116 NCT01074086 NCT01074086 NCT01154439 NCT00775593 NCT02583893 NCT01869114 NCT01822015	Phase I-II	[38,158]
Oblimersen (Genasense, G3139)	bcl-2 antisense oligodeoxynucleotide	NCT00085124 NCT00039117 NCT00017589	Phase I-III	[46,159,160]
Obatoclax Mesylate (GX15-070MS)	Small molecule bcl-2 inhibitor	NCT00438178 NCT00684918 NCT00684918	Phase I-II	[161-163]
Therapy targeting the LSC microenvironment
G-CSF	Mobilization of LSC from the protective bone marrow niche - > increased susceptibility to traditional chemotherapy	NCT00820976 NCT00602225 NCT00199147 NCT01723657 NCT01101880 NCT00943943 NCT00906945	Phase I-III	[165-168]
Plerixafor (AMD3100)	CXCR4 inhibitor Decreased homing to the bone marrow	NCT00943943 NCT00906945 NCT01236144 NCT00512252 NCT01319864 NCT01352650 NCT02416908	Phase I-II	[61,135,178]
AMD3465	CXCR4 inhibitor Decreased homing to the bone marrow	N/A	N/A	[61,135,169,179]
BMS-936564	Anti-CXCR4 antibody Decreased homing to the bone marrow	NCT01120457	Phase I	[172]
Natalizumab	Anti-VLA4 antibody Decreased homing to the bone marrow	N/A	N/A	[174]

GO: Gemtuzumab ozogamicin; DART: Dual-affinity retargeting molecule; N/A: Not available; LSC: Leukemia stem cell; IkBa: Inhibitor of kappa B alpha; CXCR4: C-X-C chemokine receptor type 4; mTOR: Mechanistic target of rapamycin; G-CSF: Granulocyte-colony stimulating factor.