“Mast”ering drug discovery with iPSCs

Dorrance, Adrienne M.

doi:10.1182/blood.2020010456

Cited by 2 publications

(2 citation statements)

References 6 publications

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“…Because of this, the presence of mutations in limited sets of genes has been included in several recently proposed risk stratification models for both AdvSM (i.e., SRSF2/ASXL1/RUNX1 [11], SRSF2/ASXL1/RUNX1/EZH2 [13], ASXL1/RUNX1/NRAS [120]) and Non-AdvSM (e.g., ASXL1/RUNX1/DNMT3A [12]). The recent development of SM-induced pluripotent stem cells (iPSCs) positive for KIT D816V and other concurrent mutations [180], which accurately reflect the genetic background of SM patients' multi-mutated pathological cells, may become a powerful tool to dissect the impact of these mutations on the aetiopathogenic mechanisms involved in disease progression [181]. Therefore, molecular characterization of the genetic background of AdvSM patients, including NGS as described above, VAF assessment of somatic mutations [125,182] and drug screening in patient-derived iPSCs [180,183], may lead to improved molecularly targeted treatment options in a context of personalized precision medicine.…”

Section: Prognostic Impact Of Acquired Gene Mutations In Systemic Mas...mentioning

confidence: 99%

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

González‐López

Muñoz‐González

Órfão

et al. 2022

Cancers

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Systemic mastocytosis (SM) is a rare clonal haematopoietic stem cell disease in which activating KIT mutations (most commonly KIT D816V) are present in virtually every (>90%) adult patient at similar frequencies among non-advanced and advanced forms of SM. The KIT D816V mutation is considered the most common pathogenic driver of SM. Acquisition of this mutation early during haematopoiesis may cause multilineage involvement of haematopoiesis by KIT D816V, which has been associated with higher tumour burden and additional mutations in other genes, leading to an increased rate of transformation to advanced SM. Thus, among other mutations, alterations in around 30 genes that are also frequently mutated in other myeloid neoplasms have been reported in SM cases. From these genes, 12 (i.e., ASXL1, CBL, DNMT3A, EZH2, JAK2, KRAS, NRAS, SF3B1, RUNX1, SF3B1, SRSF2, TET2) have been recurrently reported to be mutated in SM. Because of all the above, assessment of multilineage involvement of haematopoiesis by the KIT D816V mutation, in the setting of multi-mutated haematopoiesis as revealed by a limited panel of genes (i.e., ASXL1, CBL, DNMT3A, EZH2, NRAS, RUNX1 and SRSF2) and associated with a poorer patient outcome, has become of great help to identify SM patients at higher risk of disease progression and/or poor survival who could benefit from closer follow-up and eventually also early cytoreductive treatment.

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Section: Prognostic Impact Of Acquired Gene Mutations In Systemic Mas...mentioning

confidence: 99%

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

González‐López

Muñoz‐González

Órfão

et al. 2022

Cancers

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“…To overcome this limitation, Toledo et al generated the induced pluripotent stem cells (iPSCs) from patients with aggressive SM, which represents a new approach for disease modeling and screening for precision medicine. Using these iPSCs, the authors identified nintedanib, which is a FDA approved angiokinase inhibitor that targets the vascular endothelial growth factor receptor (EGFR) and fibroblast growth factor receptor, as a novel KIT D816V inhibitor [102,103]. Table 5 summarizes the main recruiting clinical trials in SM.…”

Section: Future Perspectivesmentioning

confidence: 99%

Precision Medicine in Systemic Mastocytosis

et al. 2021

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Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.

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“Mast”ering drug discovery with iPSCs

Cited by 2 publications

References 6 publications

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

Precision Medicine in Systemic Mastocytosis

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