iPSC modeling of stage-specific leukemogenesis reveals BAALC as a key oncogene in severe congenital neutropenia

Dannenmann, Benjamin; Klimiankou, Maksim; Oswald, Benedikt; Соловьева, А. Г.; Mardan, Jehan; Nasri, Masoud; Ritter, Malte; Zahabi, Azadeh; Arreba-Tutusaus, Patricia; Mir, Perihan; Stein, Frederic; Kandabarau, Siarhei; Lachmann, Nico; Möritz, Thomas; Morishima, Tatsuya; Konantz, Martina; Lengerke, Claudia; Ripperger, Tim; Steinemann, Doris; Erlacher, Miriam; Niemeyer, Charlotte M.; Zeidler, Cornelia; Welte, Karl; Skokowa, Julia

doi:10.1016/j.stem.2021.03.023

Cited by 16 publications

(13 citation statements)

References 61 publications

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“…Introduction of additional co-operating mutations in CSF3R or RUNX1 in reprogrammed patient cells harboring ELANE mutation identified the upregulation of BAALC and phosphorylation of MK2a as key pathological events of progression of CN to CN/AML. Targeting MK2a phosphorylation using small molecular inhibitor induced cell death in mutant cells while sparing the healthy cells, thus implying a potential prevention to progression or to avoid relapse [84]. Similarly, stepwise modeling of CH, MDS and AML, identified inflammation-related transcription factors primarily present in early stages of CH and MDS and can be targeted to kill blasts that may be responsible for relapse in AML [80].…”

Section: Identification Of Therapeutic Targets Using Ipscs-clinical and Translational Implicationsmentioning

confidence: 99%

Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies

Sidhu

Barwe

Pillai

et al. 2021

Cells

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In vitro modeling of hematological malignancies not only provides insights into the influence of genetic aberrations on cellular and molecular mechanisms involved in disease progression but also aids development and evaluation of therapeutic agents. Owing to their self-renewal and differentiation capacity, induced pluripotent stem cells (iPSCs) have emerged as a potential source of short in supply disease-specific human cells of the hematopoietic lineage. Patient-derived iPSCs can recapitulate the disease severity and spectrum of prognosis dictated by the genetic variation among patients and can be used for drug screening and studying clonal evolution. However, this approach lacks the ability to model the early phases of the disease leading to cancer. The advent of genetic editing technology has promoted the generation of precise isogenic iPSC disease models to address questions regarding the underlying genetic mechanism of disease initiation and progression. In this review, we discuss the use of iPSC disease modeling in hematological diseases, where there is lack of patient sample availability and/or difficulty of engraftment to generate animal models. Furthermore, we describe the power of combining iPSC and precise gene editing to elucidate the underlying mechanism of initiation and progression of various hematological malignancies. Finally, we discuss the power of iPSC disease modeling in developing and testing novel therapies in a high throughput setting.

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Section: Identification Of Therapeutic Targets Using Ipscs-clinical and Translational Implicationsmentioning

confidence: 99%

Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies

Sidhu

Barwe

Pillai

et al. 2021

Cells

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“…In another study, using iPSC-derived motor neuron (MN) as a disease model and CRISPR/Cas9 as a tool to correct FUS mutations, surprisingly, metabolic dysfunction was found to not be the underlying cause of the ALS-related phenotypes [ 38 ]. Establishing a stepwise model of congenital neutropenia to acute myeloid leukemia (AML), derived from congenital neutropenia patient-derived iPSCs by CRISPR/Cas9, revealed that BAALC and MK2a phosphorylation may be excellent targets for preventing leukemogenic transformation or eliminate AML blasts [ 39 ].…”

Section: Applications Of Gene Editing In Pscs and Their Organoidsmentioning

confidence: 99%

Gene Editing in Pluripotent Stem Cells and Their Derived Organoids

Zhou

Wang

Liu

et al. 2021

Stem Cells International

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With the rapid rise in gene-editing technology, pluripotent stem cells (PSCs) and their derived organoids have increasingly broader and practical applications in regenerative medicine. Gene-editing technologies, from large-scale nucleic acid endonucleases to CRISPR, have ignited a global research and development boom with significant implications in regenerative medicine. The development of regenerative medicine technologies, regardless of whether it is PSCs or gene editing, is consistently met with controversy. Are the tools for rewriting the code of life a boon to humanity or a Pandora’s box? These technologies raise concerns regarding ethical issues, unexpected mutations, viral infection, etc. These concerns remain even as new treatments emerge. However, the potential negatives cannot obscure the virtues of PSC gene editing, which have, and will continue to, benefit mankind at an unprecedented rate. Here, we briefly introduce current gene-editing technology and its application in PSCs and their derived organoids, while addressing ethical concerns and safety risks and discussing the latest progress in PSC gene editing. Gene editing in PSCs creates visualized in vitro models, providing opportunities for examining mechanisms of known and unknown mutations and offering new possibilities for the treatment of cancer, genetic diseases, and other serious or refractory disorders. From model construction to treatment exploration, the important role of PSCs combined with gene editing in basic and clinical medicine studies is illustrated. The applications, characteristics, and existing challenges are summarized in combination with our lab experiences in this field in an effort to help gene-editing technology better serve humans in a regulated manner. Current preclinical and clinical trials have demonstrated initial safety and efficacy of PSC gene editing; however, for better application in clinical settings, additional investigation is warranted.

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“…Functional genomics has also been employed for modeling non-neurological complex diseases in hiPSC-based systems, such as cancer. For example, a severe congenital neutropenia (CN) iPSC model carrying a RUNX1 mutation associated with leukemia effectively recapitulates leukemogenesis in CN ( Dannenmann et al., 2021 ). This in vitro model system is particularly important as there are currently no animal models that can recapitulate the in vivo stepwise CN transition to acute myeloid leukemia (AML).…”

Section: Introductionmentioning

confidence: 99%