PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia

Cole, Christopher B.; Verdoni, Angela M.; Ketkar, Shamika; Leight, Elizabeth R.; Russler‐Germain, David A.; Lamprecht, Tamara; Demeter, Ryan; Magrini, Vincent; Ley, Timothy J.

doi:10.1172/jci82897

Cited by 36 publications

(35 citation statements)

References 50 publications

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“…To characterize the effects of Dnmt3a haploinsufficiency on hematopoiesis, we used a previously described constitutive Dnmt3a-knockout mouse with a neomycin resistance cassette inserted into a deletion of exons 18 and 19 of the catalytic domain of Dnmt3a (17). We previously verified that this mutation produces a null allele with no detectable Dnmt3a protein by Western blotting of homozygous null embryos with an N-terminal Dnmt3a antibody (23) and determined that the bone marrow cells of these homozygous Dnmt3a -/-mice have a focal, canonical DNA hypomethylation phenotype using targeted bisulfite sequencing (23). In this study, we intercrossed heterozygous Dnmt3a +/-mice on…”

Section: Resultsmentioning

confidence: 99%

“…Kras mutation VAFs are from AmpliSeq data (Supplemental Table 6), while other mutation VAFs are from exome sequencing (Supplemental Tables 3-5 -/-mice and subjected DNA from these cells to whole-genome bisulfite sequencing, as previously described (15). Four independent bone marrow samples were evaluated from 2-week-old Dnmt3a +/+ and Dnmt3a -/-mice; previous studies in our laboratory revealed that these samples have highly similar cellular compositions (23). Samples from 6 time points were obtained from Dnmt3a +/-mice, harvested at 2 weeks, 4 weeks (2 mice), 6 weeks, 3 months, 9 months, or 1 year of age.…”

Section: Transplantable Tumors From Dnmt3a +/-Mice Retain a Functionamentioning

confidence: 99%

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Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

Cole

Russler‐Germain

Ketkar

et al. 2017

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Section: Transplantable Tumors From Dnmt3a +/-Mice Retain a Functionamentioning

confidence: 99%

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

Cole

Russler‐Germain

Ketkar

et al. 2017

Journal of Clinical Investigation

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“…This is supported by the fact that functional loss of Dnmt3a in murine hematopoietic cells causes an expansion of the stem cell pool with serial transplantation (Challen et al, 2011), implying that Dnmt3a may normally act to suppress self-renewal in progenitor cells. In patients who have clinically apparent AML, this methylation response may represent a “brake” that is overwhelmed by cooperating mutations that drive proliferation (although not all AML mutations may behave in this way (Cole et al, 2016)). The hypermethylation of CpG islands by DNMT3A may represent a molecular “fossil” of a failed attempt to restrict proliferation and/or abnormal self-renewal.…”

Section: Discussionmentioning

confidence: 99%

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

Spencer

Russler‐Germain

Ketkar

et al. 2017

Cell

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Summary DNMT3A mutations occur in ~25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3AR882H, has dominant negative activity that reduces DNA methylation activity by ~80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3AR882 mutations. Non-leukemic hematopoietic cells with DNMT3AR882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing, and was essentially absent in AMLs with DNMT3AR882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3AR882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.

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“…Nuclear bodies are stress-sensitive nuclear domains involved in p53 activation and the control of senescence [223,224]. Other functions have been attributed to PML/RARA, which is also influenced by important genetic modulators [225][226][227][228][229]. ATRA and ATO bind to the PML-RARA fusion oncoprotein and initiate proteolytic degradation of PML-RARA [222].…”

Section: Atra-ato In Frontline Therapymentioning

confidence: 99%

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

Thomas

2019

Oncol Ther

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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARa) genes. Because patients with APL present a tendency for severe bleeding, often resulting in an early fatal course, APL was historically considered to be one of the most fatal forms of acute leukemia. However, therapeutic advances, including anthracyclineand cytarabine-based chemotherapy, have significantly improved the outcomes of APL patients. Due to the further introduction of alltrans retinoic acid (ATRA) and-more recentlythe development of arsenic trioxide (ATO)containing regimens, APL is currently the most curable form of AML in adults. Treatment with these new agents has introduced the concept of cure through targeted therapy. With the advent of revolutionary ATRA-ATO combination therapies, chemotherapy can now be safely omitted from the treatment of low-risk APL patients. In this article, we review the six-decade history of APL, from its initial characterization to the era of chemotherapy-free ATRA-ATO, a model of cancer-targeted therapy.

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PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia

Cited by 36 publications

References 50 publications

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies

CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression

Acute Promyelocytic Leukemia: A History over 60 Years—From the Most Malignant to the most Curable Form of Acute Leukemia

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