Abstract
Despite enormous improvements in pre-clinical and clinical research, acute leukemia still represents an open challenge for pediatric hematologists; both for a significant relapse rate and for long term therapy-related sequelae. In this context, the use of an innovative technology, such as induced pluripotent stem cells (iPSCs), allows to finely reproduce the primary features of the malignancy and can be exploited as a model to study the onset and development of leukemia in vitro. The aim of this review is to explore the recent literature describing iPSCs as a key tool to study different types of hematological malignancies, comprising acute myeloid leukemia, non-down syndrome acute megakaryoblastic leukemia, B cell acute lymphoblastic leukemia, and juvenile myelomonocytic leukemia. This model demonstrates a positive impact on pediatric hematological diseases, especially in those affecting infants whose onsets is found in fetal hematopoiesis. This evidence highlights the importance of achieving an in vitro representation of the human embryonic hematopoietic development and timing-specific modifications, either genetic or epigenetic. Moreover, further insights into clonal evolution studies shed light in the way of a new precision medicine era, where patient-oriented decisions and therapies could further improve the outcome of pediatric cases. Nonetheless, we will also discuss here the difficulties and limitations of this model.
Highlights
Acute leukemia (AL) represents the most frequent cause of childhood cancer-related mortality worldwide, with an estimated incidence of 10 to 50 cases per 100,000 every year and a cumulative risk of 1 in 2000 up to the age of 15 [1]
As a matter of fact, these initial genes were all linked to inflammatory responses and immune signaling, and two preclinical compounds that inhibit inflammatory signaling displayed efficient activity in disrupting colony formation at all mutational stages in a dose-dependent manner, excluding the wild-type parental induced pluripotent stem cells (iPSCs)
B-cell precursor Acute lymphoblastic leukemia (ALL) (BCP-ALL) is the most frequent ALL subtype in children. It is an heterogeneous disease driven by different types of initiating genetic alterations: chromosomal aneuploidy, rearrangements, and point mutations [2] occurring in different genes, responsible for cytokine-receptor or kinase signaling, such as ABL1, ABL2, PDGFRB, CSF1R, JAK2, RUNX1, EPOR, and CRLF2 [33]. iPSCs modeling of ALL represented a harder goal compared to acute myeloid leukemia (AML)
Summary
Acute leukemia (AL) represents the most frequent cause of childhood cancer-related mortality worldwide, with an estimated incidence of 10 to 50 cases per 100,000 every year and a cumulative risk of 1 in 2000 up to the age of 15 [1]. The generation of mouse models that can mimic the prenatal origin of the disease could be an important contribution to the repertoire of research tools for pediatric leukemia, animal models still carry other important limitations in recapitulating the human leukemic phenotype, mainly due the presence of an embryonic lethality, a non-hematopoietic expression or the upraise of a lymphoma. AML primary blasts are difficult to maintain in culture as well, due to rapid differentiation and undergoing apoptosis in ex vivo cultures, and they often need the bone marrow support or addition of small molecules such as Aryl hydrocarbon suppressor [14] Given these difficulties and paucity of primary samples, new research methods are needed to investigate and deeply characterize childhood leukemias in order to better understand the underlying biology and to discover new therapeutic targets [15]
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