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Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells.
Lin, Huan-Ting; Takagi, Masatoshi; Kubara, Kenji; Yamazaki, Kazuto; Michikawa, Fumiko; Okumura, Takashi; Naruto, Takuya; Morio, Tomohiro; Miyazaki, Koji; Taniguchi, Hideki; Otsu, Makoto.
Afiliação
  • Lin HT; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan. franklin_ht_lin@hotmail.com.
  • Takagi M; Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.
  • Kubara K; Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, 300-2635, Japan.
  • Yamazaki K; Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, 300-2635, Japan.
  • Michikawa F; Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, 300-2635, Japan.
  • Okumura T; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
  • Naruto T; Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.
  • Morio T; Department of Pediatrics and Developmental Biology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan.
  • Miyazaki K; Department of Transfusion and Cell Transplantation, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan.
  • Taniguchi H; Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
  • Otsu M; Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, 236-0004, Japan.
Stem Cell Res Ther ; 15(1): 106, 2024 Apr 16.
Article em En | MEDLINE | ID: mdl-38627844
ABSTRACT

BACKGROUND:

Although oncogenic RAS mutants are thought to exert mutagenic effects upon blood cells, it remains uncertain how a single oncogenic RAS impacts non-transformed multipotent hematopoietic stem or progenitor cells (HPCs). Such potential pre-malignant status may characterize HPCs in patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). This study sought to elucidate the biological and molecular alterations in human HPCs carrying monoallelic mutant KRAS (G13C) with no other oncogene mutations.

METHODS:

We utilized induced pluripotent stem cells (iPSCs) derived from two unrelated RALD patients. Isogenic HPC pairs harboring either wild-type KRAS or monoallelic KRAS (G13C) alone obtained following differentiation enabled reliable comparative analyses. The compound screening was conducted with an established platform using KRAS (G13C) iPSCs and differentiated HPCs.

RESULTS:

Cell culture assays revealed that monoallelic KRAS (G13C) impacted both myeloid differentiation and expansion characteristics of iPSC-derived HPCs. Comprehensive RNA-sequencing analysis depicted close clustering of HPC samples within the isogenic group, warranting that comparative studies should be performed within the same genetic background. When compared with no stimulation, iPSC-derived KRAS (G13C)-HPCs showed marked similarity with the wild-type isogenic control in transcriptomic profiles. After stimulation with cytokines, however, KRAS (G13C)-HPCs exhibited obvious aberrant cell-cycle and apoptosis responses, compatible with "dysregulated expansion," demonstrated by molecular and biological assessment. Increased BCL-xL expression was identified amongst other molecular changes unique to mutant HPCs. With screening platforms established for therapeutic intervention, we observed selective activity against KRAS (G13C)-HPC expansion in several candidate compounds, most notably in a MEK- and a BCL-2/BCL-xL-inhibitor. These two compounds demonstrated selective inhibitory effects on KRAS (G13C)-HPCs even with primary patient samples when combined.

CONCLUSIONS:

Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas Limite: Humans Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas Limite: Humans Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão