Table 1.

iPSCs as disease models and applications of gene therapy or genome editing for hematological disorders.

Disorders	Affected gene(s)	Phenotype assessment	Gene therapy/correction	Ref
AML	MLL	AML-iPSCs lacked leukemic potential but reacquired the ability upon hematopoietic differentiation in vivo.	N/A	[66]
CGD	CYBB	CGD iPSC-derived neutrophils lacked ROS production.	ZFN-mediated CYBB gene correction substantially restored neutrophil ROS production.	[67]
CML	BCR-ABL	CML-iPSCs and hematopoietic cells were used as models for studying mechanism leading to leukemic stem cell survival in the presence of tyrosine kinase inhibitor.	N/A	[68–71]
DBA	RPS19 and RPL5	Mutant iPSCs exhibited defects in ribosomal subunit assembly and impaired erythropoiesis upon differentiation.	ZFN-mediated RPS19 and RPL5 gene correction alleviated abnormalities in ribosome biogenesis and hematopoiesis.	[72]
	RPS19 and RPL5	DBA-iPSCs showed altered TGFβ signaling, aberrant ribosome biogenesis, and impaired erythropoiesis when compared to the wild-type iPSCs.	Ectopic expression of both genes in the “safe harbor” AAVS1 site restored the level of SMAD4, which is the major effector of the canonical TGFβ signaling pathway.	[73]
FPD/AML	RUNX1	FPD-iPSCs are uniformly defective in hematopoietic progenitor (HP) emergence and megakaryocyte (MgK) differentiation.	Overexpression of RUNX1 rescued emergence of HP cells but partially restored MgK maturation.	[74]
HA	F8	Endothelial cells (ECs) derived from HA-iPSCs lacked F8 transcript and FVIII protein.	Targeted chromosomal inversions restored F8 transcript and FVIII protein secretion in the corrected iPSC-derived ECs.	[75–78]
	F8	Endothelial cells (ECs) derived from HA-iPSCs had undetectable levels of FVIII gene expression and secretory protein.	Lentiviral gene therapy in HA-iPSCs restored FVIII secretion in the corrected iPSC-derived ECs both in vitro and in vivo in immune-deficient HA mouse model.	[79]
HB	FIX (F9)	Hepatocyte-like cells derived from HB-iPSCs could not secrete clotting factor IX.	CRISPR/Cas9-based point correction or knock-in full-length FIX cDNA in HB-iPSCs restored clotting factor IX secretion. Upon transplantation, human albumin and factor IX were detected up to 9-12 months in a mouse model of HB.	[80]
	FIX (F9)	Hepatocyte-like cells derived from HB-iPSCs could not secrete clotting factor IX.	CRISPR/Cas9-mediated correction of FIX point mutation or targeted knock-in full-length FIX cDNA at AAVS1 locus in HB-iPSCs restored clotting factor IX secretion in the corrected iPSC-derived hepatocyte-like cells.	[81, 82]
MDS	Loss of chromosome 7q (del(7q))	MDS-iPSCs had impaired hematopoietic differentiation potential and clonogenic capacity and increased cell death upon differentiation.	Spontaneous acquisition of an extra chromosome 7 fully restored hematopoietic differentiation potential of the MDS-iPSCs.	[65, 83]
PNH	PIGA	PIGA-iPSCs were unable to produce hematopoietic cells or mesodermal cells expressing KDR/VEGFR2 and CD56 markers.	N/A	[84]
PV	JAK2 (V617F)	iPSC-derived hematopoietic cells exhibited enhanced erythropoiesis.	N/A	[63, 85, 86]
SCD	HBB	N/A	Correction of sickle point mutation by CRISPR/Cas9 or TALENs allowed HBB protein production in the corrected iPSC-derived erythrocytes.	[87, 88]
SCID-X1	JAK3	JAK3-deficient iPSCs had a complete block in early T cell development.	Correction of JAK3 gene by CRISPR/Cas9 restored normal T cell development.	[89]
	IL-2Rγ	IL-2Rγ mutant iPSCs could not differentiate to functional lymphocytes.	TALEN-mediated IL-2Rγ gene correction restored the production of mature NK cells and T cell precursors.	[90]
Thalassemia	HBB	Erythrocytes differentiated from homozygous beta thalassemia-iPSCs lacked HBB gene and protein expressions.	Correction of HBB mutation by CRISPR/Cas9 restored HBB gene and protein expression in the corrected iPSC-derived erythrocytes.	[91–93]
	HBB	Double heterozygous HbE/β-thalassemia iPSCs produced lower hematopoietic progenitor and erythroid cells than the wild-type iPSCs under feeder-free HSPC differentiation system.	Correction of HBE mutation by CRISPR/Cas9 restored the number of hematopoietic progenitor and erythroid cells.	[94]
	HBA	Homozygous alpha thalassemia iPSC-derived erythroid cells expressed no α-globin chains.	ZFN-mediated HBA gene correction resulted in restoration of globin chain imbalance in the corrected iPSC-derived erythroid cells.	[95]
WAS	WAS	WAS-iPSCs exhibited defects in platelet production.	Lentiviral gene therapy in WAS-iPSCs improved structures of proplatelet and increased the platelet size.	[96]
	WAS	WAS-iPSCs exhibited deficient T lymphopoiesis and natural killer (NK) cell differentiation and function.	ZFN-mediated WAS gene correction restored T and NK cell differentiation and function.	[97]

AML: acute myeloid leukemia; CGD: chronic granulomatous disease; CML: chronic myeloid leukemia; DBA: Diamond-Blackfan anemia; FPD/AML: familial platelet disorder/acute myeloid leukemia; HA: hemophilia A; HB: hemophilia B; MDS: myelodysplastic syndromes; PNH: paroxysmal nocturnal hemoglobinuria; PV: polycythemia vera; SCD: sickle cell disease; SCID: severe combined immunodeficiency; WAS: Wiskott-Aldrich syndrome.