Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation

Mayle, Allison; Yang, Liubin; Rodriguez, Blanca; Zhou, Ting; Chang, Edmond Chin‐Ping; Curry, Choladda V.; Challen, Grant A.; Li, Wei; Wheeler, David A.; Rebel, Vivienne I.; Goodell, Margaret A.

doi:10.1182/blood-2014-08-594648

Cited by 208 publications

(199 citation statements)

References 43 publications

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“…Overall, our data uncover a role for Dnmt3a in restraining mast cell proinflammatory responses. Discussion DNMT3A is one of the most frequently mutated genes in hematological malignancies and, due to extensive research, its role in cancer is becoming clearer (44,45). Although we found a relative increase in the ability of mast cells to proliferate in the absence of Dnmt3a, most of the major phenotypes we observed in these cells were actually linked to acute and chronic cell activation, both in vitro and in vivo.…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Mascontrasting

confidence: 44%

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

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DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.DNA methylation | epigenetics | inflammation | mast cells

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Section: Dysregulated Dna Methylation Activity Leads To Increased Mascontrasting

confidence: 44%

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

115

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“…[4][5][6] In the present study, we demonstrate that another epigenetic modifier, LSD1, acts in a similar manner to generate preleukemic stem cells for the development of T-cell malignancies. To the best of our knowledge, this is the first demonstration of a founder abnormality specific for T-cell leukemogenesis; however, it is possible that LSD1 overexpression predisposes to other types of malignancies depending on second hits, given the fact that T-LBL is the most common tumor induced by g-irradiation in B6 mice.…”

Section: Discussionmentioning

confidence: 86%

“…[4][5][6] We assumed that HSCs of LSD1 transgenic mice were also preleukemic because they exhibited an increased self-renewal potential but retained the ability of normal differentiation. It is therefore likely that LSD1 transgenic mice develop hematological malignancies, especially T-cell leukemias, when they are exposed to additional genotoxic insults.…”

Section: Lsd1 Overexpression In Quiescent Hscs Accelerates G-irradiatmentioning

confidence: 99%

“…For example, recurrent mutations of DNA methyltransferase 3A (DNMT3A) or isocitrate dehydrogenase (IDH) 1/2 give rise to preleukemic hematopoietic stem cells (HSCs), which possess a higher self-renewal potential than normal counterparts but retain multidifferentiation capacity. [4][5][6] Additional genetic abnormalities, such as nucleophosmin 1 mutations and FLT3-internal tandem duplication, confer further growth advantages and malignant phenotypes to preleukemic HSCs, leading to the development of full-blown acute myeloid leukemias (AML). Similar initiator functions have been demonstrated in other epigenetic regulators, such as the methylcytosine hydroxylase TET2, histone methyltransferase EZH2, and Polycomb-related protein ASXL2, in myeloid leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Wada

Koyama

Kikuchi

et al. 2015

Blood

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Key Points• LSD1 is barely expressed in normal hematopoietic stem cells, but is overexpressed in leukemias especially those of a T-cell origin.• LSD1 overexpression forms preleukemic stem cells with an increased self-renewal potential in a transgenic mice model.Recent investigations indicate that epigenetic regulators act at the initial step of myeloid leukemogenesis by forming preleukemic hematopoietic stem cells (HSCs), which possess the increased self-renewal potential but retain multidifferentiation ability, and synergize with genetic abnormalities in later stages to develop full-blown acute myeloid leukemias. However, it is still unknown whether this theory is applicable to other malignancies. In this study, we demonstrate that lysine-specific demethylase 1 (LSD1) overexpression is a founder abnormality for the development of T-cell lymphoblastic leukemia/ lymphoma (T-LBL) using LSD1 transgenic mice. LSD1 expression is tightly regulated via alternative splicing and transcriptional repression in HSCs and is altered in most leukemias, especially T-LBL. Overexpression of the shortest isoform of LSD1, which is specifically repressed in quiescent HSCs and demethylates histone H3K9 more efficiently than other isoforms, increases self-renewal potential via upregulation of the HoxA family but retains multidifferentiation ability with a skewed differentiation to T-cell lineages at transcriptome levels in HSCs. Transgenic mice overexpressing LSD1 in HSCs did not show obvious abnormalities but developed T-LBL at very high frequency after g-irradiation. LSD1 overexpression appears to be the first hit in T-cell leukemogenesis and provides an insight into novel strategies for early diagnosis and effective treatment of the disease. (Blood. 2015;125(24):3731-3746)

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“…Moreover, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 y and were diagnosed with a spectrum of malignancies similar to those observed in patients carrying DNMT3A mutations, including MDS, AML, primary myelofibrosis, and ALL, suggesting that Dnmt3a functions as a tumor suppressor (7). With a second hit of mutations in various genes such as N-RAS, C-KIT, or FLT3 in Dnmt3a −/− mice, Dnmt3a deletion induces leukemic transformation (14,15). Although these results indicate a major role of Dnmt3a deletion in facilitating the development of leukemia, the in vivo roles of DNMT3A mutants in leukemogenesis still need to be addressed.…”

mentioning

confidence: 99%

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

Dai

Wang

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin − Sca1 + cKit + cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G 2 /M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3a R878H/WT mice.have been identified in a subset of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), with DNMT3A R882 being the hotspot (1-4). Clinical features of most AML cases with DNMT3A mutations include preferential involvement of a monocytic lineage (AML-M4 and -M5 subtypes), thrombocytosis, onset at a relatively old age, and poor prognosis (2, 5, 6). Careful genotypephenotype correlations suggest that patients manifest DNMT3A mutations in preleukemic hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs), which exhibit a competitive advantage over normal HSCs. Because these mutations occur at a very early stage among genetic abnormalities, they are likely involved in the development of leukemia (7,8).Functionally, the DNMT3A R882 mutation might disrupt epigenetic regulation. This kind of DNMT3A mutation confers reduced methyltransferase activity and promotes the possibility of dominant-negative consequences compared with the wild-type (WT) allele (2, 9, 10). Moreover, the DNMT3A mutation causes aberrant DNA hypomethylation and up-regulates a series of target genes involved in AML pathogenesis (11-13).In vivo animal tests have shown that the Dnmt3a gene plays an essential role in hematopoiesis regulation. Dnmt3a −/− HSCs expand remarkably, but their differentiation is inhibited when Dnmt3a is conditionally inactivated in the murine hematopoietic system; this phenomenon is consistent with a preleukemic state (7). Moreover, all lethally irradiated mice transplanted with Dnmt3a-deleted HSCs died within 1 y and were diagnosed with a spectrum of malignancies similar to those observed in patients carrying DNMT3A mutations, including MDS, AML, primary myelofibrosis, and ALL, suggesting that Dnmt3a functions as a tumor suppressor (7). With a second hit of mutations in various genes such as N-RAS, C-KIT, or FLT3 in Dnmt3a −/− mice, Dnmt3a deletion induces leukemic transformation (14, 15). Although these results indicate a major role of Dnmt3a deletion in facilitating the development of leukemia, the in vivo roles of DNMT3A mutants in leukemogenesis still need to be addressed. In our previous work, b...

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Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation

Abstract: Key Points Dnmt3a ablation in HSCs predisposes mice to develop a spectrum of myeloid and lymphoid malignancies. Dnmt3a-KO-derived myeloid malignancies and T-cell acute lymphocytic leukemia/lymphoma show distinct methylation aberrations.

Cited by 208 publications

References 43 publications

Dnmt3a restrains mast cell inflammatory responses

Dnmt3a restrains mast cell inflammatory responses

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement

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