Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies
Abstract
:1. Introduction
2. Disease Modeling Using Patient-Derived iPSCs
3. Disease Modeling Using Genetically Modified iPSCs
3.1. Clonal Evolution of AML: An Example of De Novo Leukemogenesis in Human iPSCs
3.2. Down Syndrome-Myeloid Leukemia: An Example of iPSC-Based Sequential Disease Modeling
4. Identification of Therapeutic Targets using iPSCs—Clinical and Translational Implications
5. Hematopoietic Differentiation Approaches—2-Dimensional (2D) vs. 3-Dimensional (3D)
6. Perspectives and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ALL | Acute Lymphocytic Leukemia |
AML | Acute Myeloid Leukemia |
B-ALL | B-cell Acute Lymphocytic Leukemia |
cALL | Children Acute Lymphocytic Leukemia |
CAR | Chimeric Antigen Receptor |
CH | Clonal Hematopoiesis |
CLL | Chronic Lymphocytic Leukemia |
CML | Chronic Myelogenous Leukemia |
CMML | Chronic Myelomonocytic leukemia |
CN | Congenital Neutropenia |
CTCL | Cutaneous T-cell Lymphoma |
DLBCL | Diffuse Large B Cell Lymphoma |
DS-ML | Down Syndrome-Myeloid Leukemia |
ET | Essential Thrombocythemia |
FPD/AML | Familial Platelet Disorder/Acute Myeloid Leukemia |
GM-CSF | Granulocyte-Macrophage Colony-Stimulating Factor |
HGBCL | High-grade B-cell Lymphoma |
hnCD16 | High-affinity, Non-cleavable CD16 Fc receptor |
HSC | Hematopoietic Stem Cells |
HSPC | Hematopoietic Stem and Progenitor Cells |
IL15RF | Interleukin 15 Receptor Fusion |
iPSC | Induced Pluripotent Stem Cells |
JMML | Juvenile Myelomonocytic leukemia |
LSC | Leukemic Stem Cells |
mAB | Monoclonal Antibody |
MDS | Myelodysplastic Syndrome |
MGUS | Monoclonal Gammopathy of Undetermined Significance |
MM | Multiple Myeloma |
MPN | Myeloproliferative Neoplasm |
NHL | Non-Hodgkin Lymphoma |
NK | Natural Killer Cells |
NS/JMML | Noonan Syndrome/Juvenile Myelomonocytic Leukemia |
NSG | NOD SCID IL2Rgnull |
PTCL | Peripheral T-cell Lymphoma |
PV | Polycythemia Vera |
TKI | Tyrosine Kinase Inhibitors |
TMD | Transient Myeloproliferative Disorder |
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Disease | Model | Outcome | Reference |
---|---|---|---|
Acute myeloid leukemia (AML) | Conditional transgenic targeting NRAS and BCL-2 | MDS/AML transformation | [7] |
Npm1c/Dnmt3a mutant knock-in mice | Epigenetic therapy in preleukemic stage | [8] | |
Humanized NSG xenograft expressing BCR–ABL1 and MLL-AF9 | Efficient engraftment in humanized niche | [9] | |
Cell line-derived xenograft model | Epigenetic therapy in pediatric AML | [10] | |
Acute lymphoblastic leukemia (ALL) | Cre-recombinase-inducible mouse model for PRDM14 | Rapid onset T-ALL model | [11] |
Humanized NSG xenograft expressing MLL-AF9 | Efficient engraftment in humanized niche, efficacy of the I-BET151 inhibitor | [9] | |
T-ALL xenograft model | Targeted monoclonal antibody against NOTCH1 | [12] | |
CD81 knockout cell line xenograft | Role of CD81 in homing and engraftment | [13] | |
Chronic myeloid leukemia (CML) | Transposon-based insertional mutagenesis | Identification of mechanisms of blast crisis | [14] |
Conditional gene knock-out strains | Identification of tumor repressor PTEN in BCR-ABL background | [15] | |
Chronic lymphocytic leukemia (CLL) | NSG xenograft mice | Effect of BTK inhibitor ibrutinib | [16] |
Serial transplantation in TCL-1 transgenic mice | Efficacy of programmed cell death (PD-1) immune checkpoint inhibitors | [17] | |
Multiple myeloma (MM) | Vk*MYC transgenic mice | Identification of novel drugs | [18] |
BCL2L10 transgenic mice | Recapitulation of MM phenotype for validation of new therapies | [19] | |
B-cell lymphoma | Conditional transgenic for MYC and RAS | Preclinical testing for CD20 | [20,21] |
Follicular lymphoma | Transgenic linked to Vav regulatory sequence | Development of germinal center hyperplasia followed by follicular lymphoma | [22] |
Peripheral T-cell lymphoma (PTCL) | Inducible transgenic for ITK-SYK | Efficacy of Syk inhibitors | [23] |
Cutaneous T-cell lymphoma (CTCL) | Transgenic for IL15 | Efficacy of HDAC inhibitors | [24] |
Disease | Model | Outcome | Reference |
---|---|---|---|
Acute myeloid leukemia (AML) | SRSF2-ASXL1-NRAS triple mutant | Mechanism of clonal evolution and identification of early target genes | [80] |
RUNXI S291fs300X mutant | Blocked granulocytic differentiation via CEBPA downregulation | [81] | |
RUNX1-RUNX1T1 fusion | Blocked granulocytic differentiation via altering the acetylome during differentiation | [82] | |
Congenital neutropenia (CN)/AML | ELANE mutant knock-out | Revert the maturation arrest | [83] |
CSF3R or RUNX1 mutant | MK2a phosphorylation targeting | [84] | |
Polycythemia vera (PV) | JAK2 V617F mutant | Erythrocytosis and thrombocytosis; interferon alpha and arsenic trioxide | [85] |
JAK2 exon 12 N542-E543del mutant | Erythrocytosis; interferon alpha and arsenic trioxide therapy | [85] | |
Acute lymphoblastic leukemia (ALL)—pediatric | ETV6-RUNX1 | Initiation model during fetal development | [86] |
Transient myeloproliferative disorder/Down syndrome myeloid leukemia—pediatric | Trisomy 21 + GATA1 mutant | Initiation and progression model | [87,88,89] |
Therapy | Features | Disease | Clinical Trial Identifier |
---|---|---|---|
FT516 | NK cells expressing hnCD16 | AML | NCT04023071 |
NK cells expressing hnCD16 + mAB (rituximab or obinutuzumab) | B-lymphoma | NCT04023071 | |
FT596 | NK cells expressing hnCD16, IL15RF + mAB (rituximab) | NHL, DLBCL, HGBCL | NCT04555811 |
NK cells expressing hnCD16, IL15RF +/− mAB (rituximab or obinutuzumab) | CLL, B-lymphoma | NCT04245722 | |
iCAR NK Cells | Anti-CD19 | B-lymphoma | NCT03824951 |
FT819 | A novel 1XX CAR targeting CD19 inserted into the T-cell receptor alpha constant (TRAC) locus and edited for elimination of T-cell receptor (TCR) expression | CLL, B-lymphoma, B-ALL | NCT04629729 |
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Sidhu, I.; Barwe, S.P.; Pillai, R.K.; Gopalakrishnapillai, A. Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies. Cells 2021, 10, 2698. https://doi.org/10.3390/cells10102698
Sidhu I, Barwe SP, Pillai RK, Gopalakrishnapillai A. Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies. Cells. 2021; 10(10):2698. https://doi.org/10.3390/cells10102698
Chicago/Turabian StyleSidhu, Ishnoor, Sonali P. Barwe, Raju K. Pillai, and Anilkumar Gopalakrishnapillai. 2021. "Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies" Cells 10, no. 10: 2698. https://doi.org/10.3390/cells10102698
APA StyleSidhu, I., Barwe, S. P., Pillai, R. K., & Gopalakrishnapillai, A. (2021). Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies. Cells, 10(10), 2698. https://doi.org/10.3390/cells10102698