Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

By Kelly Moran-Crusio, Linsey B. Reavie, A. Shih, O. Abdel-Wahab, Delphine Ndiaye-Lobry, Camille Lobry, Maria E. Figueroa, A. Vasanthakumar, Jay P. Patel, Xinyang Zhao and 14 more. Cancer Cell, 2011

1,304 citations recorded by the source corpus.

SUMMARY Somatic loss-of-function mutations in the ten-eleven-translocation-2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in the hematopoietic compartment have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment which leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2+/− mice also displayed increased stem cell self-renewal and extramedulary hematopoiesis, suggesting Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.

Subfields: Hematology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bcd1c94fccfb88766ccea43fad0b79119effac8a

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In Hematology

1. Yi Zhang
2. Hao Wu
3. M. Dawson
4. Benjamin L. Ebert
5. Tony Kouzarides
6. Grant A. Challen
7. Margaret A. Goodell
8. A. Young

In Immunology

1. Yi Zhang
2. Hao Wu
3. Christoph Bock
4. Siddhartha Jaiswal

In Molecular Biology

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2. Yi Zhang
3. Chuan He
4. Christoph Bock
5. K. Helin
6. W. Kaelin
7. Tony Kouzarides
8. Jianjun Chen

Citations in the corpus

• One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering (2013, neutral): “Tet proteins (Tet1/2/3) convert 5-methylcytosine (5mC) to 5hydroxymethylcytosine (5hmC) in various embryonic and adult tissues and mutant mice for each of these three genes have been produced by homologous recombination in ES cells (Dawlaty et al., 2011; Gu et al., 2011; Li et al., 2011; Moran-Crusi”
• Influence of Metabolism on Epigenetics and Disease (2013, positive): “In addition, TET2 inactivation is sufficient to promote hematopoietic stem cell self-renewal and to block differentiation (Figueroa et al., 2010; Li et al., 2011;Moran-Crusio et al., 2011; Noushmehr et al., 2010; Turcan et al., 2012; Losman et al., 2013).”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “Mouse genetic studies have demonstrated that Tet2-deficiency causes enhanced self-renew of hematopoietic stem cells (Ko et al., 2011; Li et al., 2011; Moran-Crusio et al., 2011; Quivoron et al., 2011), supporting a role of TET2 as tumor suppressor for leukemia.”
• Cancer epigenetics: from mechanism to therapy. (2012, background): “Interestingly, TET2deficient mice develop a chronic myelomonocytic leukemia (CMML) phenotype, which is in keeping with the high prevalence of TET2 mutations in patients with this disease (Moran-Crusio et al., 2011; Quivoron et al., 2011).”
• WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, background): “, 2011); differentiation of hematopoietic cells (Ko et al., 2011; Li et al., 2011; Moran-Crusio et al., 2011; Quivoron et al., 2011); and induced pluripotent stem cell reprogramming (Costa et al.”
• Clonal hematopoiesis in human aging and disease (2019, positive): “Stem cells from these mice can grow colonies in vitro for several passages, whereas wild-type stem cells quickly lose this capacity, suggestive of enhanced self-renewal capacity in the mutant stem cells (55, 56).”
• Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal (2014, background): “…are unknown, Tet2 mutation leads to expansion of hematopoietic progenitors and increased stem cell self-renewal (Ko et al., 2011; Li et al., 2011; Moran-Crusio et al., 2011; Quivoron et al., 2011), and TET2 is recurrently mutated in myelodysplastic syndrome (MDS) and acute myeloid lymphoma (AML)…”
• Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults (2016, positive): “Comparably, TET2 loss-of-function mutations in mice increase HSC self-renewal and proliferation 28 .”