Activated <i>KRAS</i> Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

Prieto, Cristina; Stam, Ronald W.; Agraz-Doblás, Antonio; Ballerini, Paola; Camós, Mireia; Castaño, Julio; Marschalek, Rolf; Bursen, A; Varela, Ignacio; Bueno, Clara; Menéndez, Pablo

doi:10.1158/0008-5472.can-15-2769

Cited by 41 publications

(41 citation statements)

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“…Leukemia-specific translocations and recurrent genetic abnormalities have been found in both MSCs and endothelial cells in B-cell ALL, MM, and lymphoma, suggesting that stromal cells may be in part tumor related and that such oncogenic insults may arise in a population of pre-hematopoietic precursors such as early mesodermal precursors or hemangioblast-like progenitors (Blau et al., 2007, Corre et al., 2007, Lopez-Villar et al., 2009, Menendez et al., 2009, Prieto et al., 2016, Shalapour et al., 2010, Streubel et al., 2004, Walkley et al., 2007). The presence of AML-specific molecular hallmarks in BM-MSCs from AML patients has not been analyzed to date.…”

Section: Discussionmentioning

confidence: 99%

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

et al. 2017

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SummaryBone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution.

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Section: Discussionmentioning

confidence: 99%

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

et al. 2017

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“…Direct transfection of IL-3 dependent, non-malignant cell lines derived from Fancd2 −/− long-term cultures with a plasmid containing both E6/E7, transformed 8 of 164 single cells to factor independence and the malignant phenotype. Increased growth and migration capacity, but not malignant transformation has been detected in KRAS transfected cord blood cells [70]. Whether hematopoietic growth factors other than IL-3 also stimulate malignant transformation of subcultured K14E7 Fancd2 −/− marrow cells from LTBMCs is not known.…”

Section: Discussionmentioning

confidence: 99%

Evolution of malignant plasmacytoma cell lines from K14E7 Fancd2−/− mouse long-term bone marrow cultures

et al. 2016

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We tested the effect of expression of the Human Papilloma Virus (HPV E7) oncogene on hematopoiesis in long-term bone marrow cultures (LTBMCs) derived from K14E7 (FVB) Fancd2−/− (129/Sv), K14E7 Fancd2+/+, Fancd2−/−, and control (FVB X 129/Sv) Fl mice. K14E7 Fancd2−/− and Fancd2−/− LTBMCs showed decreased duration of production of total nonadherent hematopoietic cells and progenitors forming day 7 and day 14 multilineage CFU-GEMM colonies in secondary cultures (7 wks and 8 wks respectively) compared to cultures from K14E7 Fancd2+/+ (17 wks) or control mice (18 wks) p < 0.0001. Marrow stromal cell lines derived from both K14E7 Fancd2−/− and Fancd2−/− cultures were radiosensitive, as were IL-3 dependent hematopoietic progenitor cell lines derived from K14E7 Fancd2−/− cultures. In contrast, Fancd2−/− mouse hematopoietic progenitor cell lines and fresh marrow were radioresistant. K14E7 Fancd2−/− mouse freshly explanted bone marrow expressed no detectable K14 or E7; however, LTBMCs produced K14 positive factor-independent (FI) clonal malignant plasmacytoma forming cell lines in which E7 was detected in the nucleus with p53 and Rb. Transfection of an E6/E7 plasmid into Fancd2−/−, but not control Fancd2+/+ IL-3 dependent hematopoietic progenitor cell lines, increased cloning efficiency, cell growth, and induced malignant cell lines. Therefore, the altered radiobiology of hematopoietic progenitor cells and malignant transformation in vitro by K14E7 expression in cells of the Fancd2−/− genotype suggests a potential role of HPV in hematopoietic malignancies in FA patients.

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“…iPAX7‐pSAM2 and rTtA‐pSAM lentivectors used for SkM specification were kindly provided by Prof. Rita Perlingeiro (University of Minnesota). Viral particles were generated on 293T cells by Polyethylenimine or calcium phosphate transfection (along with psPAX2 and VSV‐G helper plasmids) and concentrated by ultracentrifugation, as previously described .…”

Section: Methodsmentioning

confidence: 99%

Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency

et al. 2017

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Coenzyme Q10 (CoQ10) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC) and is an essential antioxidant. Mutations in genes responsible for CoQ10 biosynthesis (COQ genes) cause primary CoQ10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype–phenotype association, mainly affecting tissues with high‐energy demand including brain and skeletal muscle (SkM). Here, we report a four‐year‐old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G > C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ10], CoQ10 biosynthesis, MRC activity affecting complexes I/II + III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4‐iPSCs) were generated, characterized and genetically edited using the CRISPR‐Cas9 system (CQ4ed‐iPSCs). Extensive differentiation and metabolic assays of control‐iPSCs, CQ4‐iPSCs and CQ4ed‐iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ10 deficiency‐associated functional and metabolic phenotypes caused by COQ4 mutation. Stem Cells 2017;35:1687–1703

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Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

Cited by 41 publications

References 50 publications

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

Evolution of malignant plasmacytoma cell lines from K14E7 Fancd2−/− mouse long-term bone marrow cultures

Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency

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