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Review Article Iran J Ped Hematol Oncol. 2019, Vol 9. No 2, 117-130

Induced pluripotent stem cells (iPSCs) based approaches for hematopoietic cancer therapy

Bardia Khandany BSc1, Mohammad Mehdi Heidari PhD1,*, Mehri Khatami PhD1

1. Department of Biology, Faculty of Science, Yazd University, Yazd, Iran. *Corresponding author: Dr Mohammad Mehdi Heidari, PhD, Department of Biology, Faculty of Science, Yazd University, Pajoohesh Street, Yazd, Iran. Email: [email protected].

Received: 23 Dcember 2018 Accepted: 02 March 2019

Abstract Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells through numerous factors. Human induced pluripotent approaches are developing as a hopeful strategy to improve our knowledge of genetic association studies and the underlying molecular mechanisms. Rapid progression in stem cell therapy and cell provides compelling reasons for its feasibility for treating a wide range of diseases through the replacement of autologous cells. Continuous failure in embryonic stem cells (ESC) production and the dependency of iPSC on ectopic genes may be due to the inability to maintain the stability of the endogenous gene systems which are essential for creation of pluripotency state. With recent developments in the genome processing and human tissue culturing approaches as well as xenotransplantation, bioengineering, and genome editing, induced pluripotent stem cells offer the new opportunities for the study of human cancers. Most hematopoietic malignancies are originated from cells that are functionally heterogeneous and few of them are responsible for maintaining tumor state. The naming of these cancer stem cells are due to the quality characteristics of normal tissue stem cells, such as self-renewal, long term survival, and the ability to produce cells with more differentiated properties. The aim of present study was to focus on the recent progresses in the application of stem cell-based hematopoietic cancer, and to assess the benefits of treatment, opportunities, and shortcomings that can potentially help improve future efforts in experimental and clinical studies. Keywords: Gene therapy, Hematopoietic cancer, Induced pluripotent stem cells

Introduction conditions that allowed specialized adult The human body comprises of over two cells to be genetically “reprogrammed” to hundred different types of cells that form accept a stem cell-like state (6). These tissues and organs and provide all the specialized cells, which are now called essential functions for survival and induced pluripotent stem cells (iPSCs), , reproduction (1). All of cells in the body, were reprogrammed to an embryonic stem both somatic (of all three germ layers) and cell-like state via introducing important germ cells, originate from the embryonic genes to maintaining the critical properties pluripotent cells (2). In 1961, for the first of embryonic stem cells (ESCs) (7). After time, Till and McCulloh (3) introduced this discovery, researchers have improved the generation techniques of iPSCs and Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] self-renewal properties in any living cells as one of their important breakthrough. created powerful new pathways to de- They influenced the mice with lethal differentiate cells, which their growth and radiation doses and then injected bone developmental conditions was already marrow cells in mice. They found that the determined (8-10). The main focus of main reason of survived of the mice was worldwide investigators and clinicians is these cells formed clumps due to cell on the potential use of iPSCs as a helpful cloned from them (4, 5). In 2006, Japanese tool for disease modeling, drug researchers at Kyoto University recognized development, and regenerative medicine Hematopoietic cancer therapy with induced pluripotent stem cells

(11-13). Furthermore, the ethical issues from somatic tissues of the rat and monkey related to the ESCs generation are not (27-29). applied to iPSCs, proposing a non- Several methods have been considered for controversial strategy to create pluripotent improving the effectiveness of the cells using existing non-pluripotent cell reprogramming and reducing the lines which can be transplanted into the potentially harmful side effects of the patients without the concern of immune reprogramming process (30). Since the rejection (autologous graft) (14, 15). used to deliver the four However, there are many challenges in transcription factors in the earliest studies pre-temporary iPSC tests, one of which is can be potentially mutagens, researchers development or tumorigenesis are not certain about whether all four risk if they are inserted in sensitive sites factors are absolutely essential (23, 31, such as promoters and host gene enhancers 32). Specially, the c- gene is known to (16). increase the rate of tumor growth in some cases, which negatively affects iPSC Experimental strategies for iPSCs efficiency in transplantation treatments generation (27, 33). For this purpose, researchers One strategy to achieve iPSCs generation proposed a three-factor approach using is nuclear reprogramming, a stable Oct4 with the orphan nuclear receptor alteration in the nucleus of a mature cell, Esrrb and , and they were able to which can then be preserved and replicated transform mouse embryonic as the cell divides through mitosis (17). into iPSCs. Similarly, other reports have This strategy is implemented using indicated that c-Myc has not a functional techniques such as fuse somatic cells with role for direct reprogramming of mouse ESCs, nuclear transfer fibroblasts (34, 35). Studies have further (SCNT), and altered nuclear transfer reduced the number of essential genes for (ANT) (18, 19). The nuclear reprogramming, and investigators continue reprogramming approach involves the use to recognize of chemicals that can replace of mature “somatic” cells from an adult or increase the efficiency of transcription and the introduction of genes that encoding factors in this procedure (36, 37). These critical proteins that successes continue to inform and facilitate themselves regulate the function of other the reprogramming process, thus important genes in the early developmental advancing the field toward the production stages of the fetus (20, 21). of patient specific stem cells for clinical In the previous studies, it was found that application. However, the way through only four transcription factors (Oct4: which transcription factors transfer to the Octamer binding transcription factor-4, somatic cells is critical to their potential Sox2: Sex determining region Y-box2, use in the clinic (38). : Krupple like factor 4, and c-Myc) were required for reprogramming of IPSCs in cancer therapy: mouse fibroblasts to an embryonic stem opportunities and challenges Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] cell–like state by forcing them to express Normally derived iPSCs from patient important genes for maintenance of the tissues can mainly be employed for tumor defining properties of ESCs (22-24). In regeneration or treatment of the affected 2007, two different research teams reached tissues. In regenerative medicine, a new milestone through deriving iPSCs numerous tissues can be produced by from human cells and using the original using iPSCs (2, 39). IPSCs therapy may be four genes containing Oct4, Sox2, Nanog, a good alternative for damaging and Lin28 (25, 26). Since then, researchers approaches such as chemotherapy, have achieved the production of iPSCs radiotherapy, or surgical treatment.

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However, regenerative therapy mediated researchers paid special attention to the by human iPSCs needs strong in vivo pluripotent stem cells that might be highly evidence from iPSC-derived tissues (19, tumorigenic. However, recently it is shown 40). that iPSCs is safer for clinical use than Now, only a few types of human iPSC- ESCs and other stem cells (49). However, derived cells (e.g. ) have been various strategies are used to minimize the effectively assessed in vivo (41, 42). In risk and possibility of neoplastic addition to the direct role of iPSCs in transformation. cancer treatment, they can be utilized to In the first step, undifferentiated screen novel anticancer drugs. Derived pluripotent stem cells, which are iPSCs from differentiating cancer tissue potentially tumorigenic, can be separated generate cell types that may be more from clinical approaches using biologically linked to human tumors and that focus on specific surface-displayed be more suitable for drug screening biomarkers. Stem cell differentiation methods. IPSCs are also better candidates downregulates expression of these than other stem cells for evaluation of the biomarkers (50). toxicities of antitumor drugs (25, 37, 43). Second, of iPSCs Similar to most chemotherapy involves monitoring of the expression of components, stem cell therapy using a the specific differentiation genes. single agent commonly cannot eliminate Successfully differentiated cells can be tumors. Therefore, a desired drug recognized and screened by using combination should be rationally generated recombinant reporter proteins. Green and selected (44, 45). Many of these fluorescent protein (GFP) and similar combination therapies have been tested to proteins work well as reporters of improve treatment durability. For example, differentiated against undifferentiated chemotherapy combined with interferon cells (51). Third, -guided toxins or (IFN)-beta immunotherapy, by using a toxic antibodies can kill the pro-drug/suicide gene system, has undifferentiated pluripotent stem cells displayed synergistic therapeutic effects in through immune pathways. For instance, human colorectal cancer (44, 46). In 2011, monoclonal antibodies against claudin-6, a Zielske et al., found that irradiating tumor surface biomarker for undifferentiated cells could induce production of factors pluripotent ESCs and iPSCs, can guide that stimulate stem cell invasion and immune-toxins to these stem cells for increase the number of stem cell in tumors targeted and selective killing (52). (47). Fourth, undifferentiated pluripotent stem There are three possibilities for tumors in cells can be removed from cytotoxic which cancer stem cells play a critical role. components, which can be utilized to kill First, the mutations in the normal stem targeted and selectively pluripotent stem cells or progenitor cells and transformation cells that can progress into tumors (53). of them into cancerous stem cells which Fifth, potentially tumorigenic pluripotent can lead to the growth of the primary stem cells can be transformed with suicide

Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] tumor. Second, many of the primary tumor genes for sensitization towards pro-drugs. cells may be killed during chemotherapy, For this purpose, the enzyme/pro-drug but if the cancerous stem cells are not cancer therapy strategies can be improved eliminated, they become cancer-resistant to kill undifferentiated pluripotent stem stem cells and may result in tumor cells (54) Finally, tumorigenic pluripotent recurrence. Third, the cancer stem cells stem cells can be eradicated through self- may emigrate to distal positions from the induced transgenic expression of primary tumor and cause metastasis (48). recombinant human DNases (55). These For these reasons, most previous

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strategies can protect a large population of patient (64). Kim et al., reported stem cells against tumor transformation. generation of single iPSC-like line in the parental pancreatic ductal adenocarcinoma Application of iPSCs in (PDAC) cancer cultures that contained regenerative medicine for cancer KRAS G12D mutation (65). The rarity of therapy successful studies demonstrates the difficulty of reprogramming primary It is proven that reprogramming of human cancer cells to iPSCs. However, technical primary cancer cells is very difficult. limitations, such as complications in However, there have been relatively few maintenance primary cancer tissues in reports demonstrating iPSCs production culture, cannot be excluded; furthermore, for successful reprogramming of tumoric the basic biological barriers may directly human cells. The generation of novel iPSC undermine the reprogramming process in and reprogramming cancer cells are cancer cells. thought to be faced with difficulties such In addition to particular characteristic of as reprogramming-triggered cellular pluripotent stem cells, such as their self- senescence, tumor-specific genetic renewal and differentiation capabilities, mutations, epigenetic modifications, they can repair human tissues after genomic instability, and accumulation of chemotherapy (66). Clinically, after DNA damage. In spite of these difficulties, treatment of malignancies with high-dose several researchers have reported the radiotherapy or chemotherapy, generation of new iPSC lines from present transplanting human stem cells has been cancer cell lines. Reports of iPSC lines generally used to facilitate lifelong resulting from human cancer cell lines are hematological recovery (67). The aim of summarized in Table I, which presents a this treatment is to reconstitute the bone range of cancers such as leukemia (AML) marrow under conditions of marrow (56), breast cancer (57), retinoblastoma failure (for example, in aplastic anemia or (58), colon cancer (44), Lliver cancer (59), other blood cell genetic diseases) and to hematologic and solid malignancies (60), apply human stem cells that differentiate melanoma (61), myelomonocytic leukemia into a desired type of hematopoietic cells (62), and glioblastoma (63). Based on in recipients (68). Normally originated these studies, reprogramming of cells with iPSCs from patient tissues can human cancer cell lines is not an theoretically be utilized to regenerate impossible task. However, certain types of tumor- or treatment- damaged tissues (69). cancers may be commonly used against In regenerative medicine approaches, reprogramming factors and the different tissues can be produced using combination of factors should be carefully iPSCs. IPSC therapy in regenerative selected depending on the type of cancer medicine may be valuable in replacing or cells that are attempting to reprogram. repairing cancer damaged cell by Nevertheless, reports of iPSCs generated radiotherapy, chemotherapy, or surgical from human primary malignant cells are treatment (70). However, regenerative few and limited to certain cancers, Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] therapy mediated by human iPSCs needs especially leukemia. Hu et al., were in vivo extensive studies in iPSC-derived successful in reprogramming primary tissues. So far, only a small number of human lymphoblasts using transgene-free human iPSC-derived cells, such as iPSC technology to ectopically express hepatocytes, have been successfully OSKM, LIN28, NANOG, and the SV40 evaluated in vivo (71, 72). large T gene from a BCR–ABL+ CML

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Table I: Applications of iPSCs in cancer therapy Origin cells used for Reprogramming factors Cancer type Type of therapy generation of iPSC Hematopoietic cells OSKM Leukemia investigating the mechanistic basis (Primary AML cells) and clonal properties of human AML, leukemic DNA methylation/gene expression patterns BRCA1-deleted blood OSKM breast cancer Cancer development modeling cells

Skin cells from RB OSNL Retinoblastoma Cancer development modeling patient

Familial OSKM Colon cancer Modeling of drug Testing in adenomatous Colorectal Cancer polyposis (Colonic )

Hepatic cells OSKM Liver cancer The engraft the liver in a mouse transplantation model

Natural killer cells (BJ1- OKSM hematologic Anti-tumor therapy (tumor targeting) iPS12, UCBiPS7, and and solid DRiPS16) malignancies

human tumor antigen- OSKM melanoma Anti-tumor therapy(tumor targeting) specific T cells (CD8+ mature T-cells)

Dendritic cells (cell lines: OSKM, BMP4 immunological Cancer immunotherapy such as DC- 201B7, 253G4, disorders based vaccines CIRA188Ai-W2, and CB- A11)

Juvenile Myelomonocytic OKSM Myelomonocyti Cancer development modeling Leukemia (JMML) c Leukemia

glioblastoma (neural OSKM, Oct4 glioblastoma Cancer development modeling lineage)

enucleated oocyte, and applying the IPSCs and hematopoietic cancer expression of specific reprogramming Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] therapy genes in somatic cells (74, 75). These two methods are used to reprogram multiple Developments in nuclear reprogramming various cell types, including pancreatic β of somatic cells lead to new ways of cells, liver cells, fibroblasts, T and B creating pluripotent stem cell lines and cells, and neural progenitor represent a significant step in the cells (76-78). Although many types of production of stem cell-based specific cells can be under nuclear reprogramming, therapies (73). Pluripotency the fundamental differences between reprogramming approach is based on pluripotent stem cell lines derived from transfer of a somatic cell nucleus into an

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distinct somatic cell types are largely researches of cancer immunotherapy (88- unclear. 90). Patient-specific iPSCs can be also An immune-mediated antitumor effect potentially helpful in immunotherapy resulting from allogeneic hematopoietic methods (91, 92). The pre-rearranged TCR stem cell (HSC) transplantation might be gene is reserved in T lymphocyte-derived appropriate for the treatment of some human iPSCs, which can be further hematological malignancies, such as CML, differentiated into functionally active T ALL, AML, Hodgkin and Non-Hodgkin cells (93, 94). lymphoma, multiple myeloma (MM), In recent years, various technologies, sickle cell anemia, thalassemia, and generally based on reversing Fanconi anemia (79-81). These HSCs are immunosuppression, have been expanded the most common multipotent stem cells by utilizing transferring cytotoxic T that can differentiate to all blood cell lines lymphocyte (CTL) (95) and transferring through hematopoiesis process (82, 83). TCR gene (96). It is also necessary that After Yamanaka studies in the field of they differentiate into double positive cells reprogramming, which led invention of (CD4/8+), before generating iPSC-derived iPS technology, many researchers have CTL (iCTL), by IL-2 which is the major tried to generate induced hematopoietic in T-cell differentiation (97, 98). stem cells (iHSC) derived from patients Experimentally tumor antigen-specific T with blood malignancy (84, 85). can be generated by Additionally, these researchers have reprogramming designated T cells into shown that the specific expression of 13 iPSCs which are then differentiate back transcription factors such as OCT4 of into T lymphocytes for infusion in OKSM factors can generate HSC. patients. However, the safety of - Recently, it has been proven that new derived human iPSCs must be more genetic engineering tools can be used for credible (99, 100). producing of iHSCs, including CRISPR- Since most cancers in a specific tissue , meganucleases, zinc-finger include acquired nucleotide mutations, nucleases (ZFN), double-strand break iPSCs resulted from other normal tissues (DSB) nucleases, and transcription of the same patient hypothetically can be activator-like effector nucleases (TALEN) used to regenerate those injured tissues by (86, 87). Studies have revealed that two the tumors themselves or subsequent transcription factors (HOXA and ERG) act treatments (101, 102). However, as the core proliferation and differentiation applications the iPSC-derived tissues in factors in HSC and are inducers of the self- cancer therapy, needs that confiremed by renewal ability, and thus dysregulation of in vivo studies. It has been made clear that these factors progresses several types of human iPSCs derived from T lymphocytes leukemic cells (85). The main differential maintain the pre-rearranged T cell receptor marker of hematopoietic stem cells is (TCR) gene; therefore, these iPSCs can be CD34 that help distinguish iHSC in induced for differentiation into association with other differentiation functionally active T cells (93, 94). In

Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] markers such as CD34, CD38, CD45, 2018, Chao et al., described the generation CD90, CD105, CD133, and C-kit (stem of AML-iPSCs from two patients, with cell receptor) (83). more emphasis on the notion that reprogramming of primary leukemias was 1- Reprogrammed T-lymphocytes not an unimportant assignment (103). Presenting genes encoding chimeric Nevertheless, natural or technical antigen receptors (CARs) or T-cell reprogramming difficulties are significant receptors (TCRs) directed against tumor- barriers to reprogramming of primary related antigens makes HSCs attractive for

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acute leukemic cells that need further able to produce large numbers of UCB investigation. CD34+ cells-derived NK-cells for adoptive The differences in reprogramming pre- immunotherapy in large-scale bioreactors, rearranged cells in AML and B-ALL and for the use in future clinical cancer propose that epigenetic reprogramming trials (116, 117). According to the studies may be dependent on the specific genetic on induced NK cells based on iPSC (iNK alterations and leukemia tumor subtype cells), reprogrammed NK cell can supply (104-106). Recent studies have shown that the desired volume of cell product to be dendritic cells derived from human iPSCs used in leukemia therapy panel without can be completely functional for the any immunological response. assessment of hematopoietic diseases (107-109). However, these cells still need Conclusion in vivo testing to confirm the effectiveness Induced pluripotent stem cells provide an and safety of their application. alternative approach to human embryonic stem cells (hESCs) without any ethical 2- Induced NK Cells concerns and with universal usage. Since Human natural killer (NK) cells are they are obtained from dedifferentiation of considered as an significant part of the adult cells and not from , iPSCs innate by producing overcome the ethical hurdles of embryonic significant for killing virally stem cells. There are still significant infected and/or malignant cells (110). obstacles that need to be considered. While antitumor T‐cell immune responses Despite the attractive research on iPSC- involve a diagnostic initiating phase and derived cell transplantation in the grafts, their responses are restricted to human there is still a potential risk of tumor leukocyte antigen (HLA), mature NK cells formation. It is possible to generate patient effectively kill malignant cells without any specific iPSC from somatic tissues, which previous exposure (111). In addition, NK can contribute to drug development, cells are the link between innate and disease modeling, and autologous stem adaptive immune systems that can increase cell therapy. Stem cells migrate to solid and accelerate immunologic responses tumors and facilitate site-specific anti- using their memory ability. At present, tumor drug delivery. It is clear that these cells are extracted by leukapheresis induced hematopoietic stem cells -derived from the blood circulation and then immune cells provide a genetic separated from other cells via magnetic manageable system to study human beads coated with anti-CD56. Both NK immune cell function and progress. In cell ‐ and T cell ‐based adoptive addition, these immune cells provide a immunotherapies have been used to treat main source of lymphocytes and may open patients with tumor malignancies. In recent new doors for cancer therapy. Finally, + studies, CD34 hematopoietic progenitor these studies have demonstrated that cell cells derived from umbilical cord blood reprogramming in primary tumor cells is (UCB) are also being used as a basis for more difficult, and that further Downloaded from ijpho.ssu.ac.ir at 5:39 IRST on Tuesday September 28th 2021 [ DOI: 10.18502/ijpho.v9i2.611 ] the generation of many numbers of technological development is needed to be allogeneic NK cells (112). Some research able to generate reliable iPSC models of groups have defined various protocols for cancers. + the production of NK cells from CD34 cells using culture of stromal cell lines and Conflicts of interest a combination of cytokines that progress There are no conflicts of interest. the expansion of NK cells (113-115). Furthermore, other researchers have been

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