DOT1L inhibitors block abnormal self-renewal induced by cohesin loss
Abstract Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for pati...
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Nature Portfolio
2021
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oai:doaj.org-article:4bea0347dc9d49beb5298d2cdd70741f2021-12-02T14:25:32ZDOT1L inhibitors block abnormal self-renewal induced by cohesin loss10.1038/s41598-021-86646-92045-2322https://doaj.org/article/4bea0347dc9d49beb5298d2cdd70741f2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86646-9https://doaj.org/toc/2045-2322Abstract Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.Katelyn E. HeimbruchJoseph B. FisherCary T. StellohEmily PhillipsMichael H. ReimerAdam J. WargoletAlison E. MeyerKirthi PulakantiAaron D. VinyJessica J. LoppnowRoss L. LevineJohn Anto PulikkanNan ZhuSridhar RaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021) |
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DOAJ |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Katelyn E. Heimbruch Joseph B. Fisher Cary T. Stelloh Emily Phillips Michael H. Reimer Adam J. Wargolet Alison E. Meyer Kirthi Pulakanti Aaron D. Viny Jessica J. Loppnow Ross L. Levine John Anto Pulikkan Nan Zhu Sridhar Rao DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
| description |
Abstract Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations. |
| format |
article |
| author |
Katelyn E. Heimbruch Joseph B. Fisher Cary T. Stelloh Emily Phillips Michael H. Reimer Adam J. Wargolet Alison E. Meyer Kirthi Pulakanti Aaron D. Viny Jessica J. Loppnow Ross L. Levine John Anto Pulikkan Nan Zhu Sridhar Rao |
| author_facet |
Katelyn E. Heimbruch Joseph B. Fisher Cary T. Stelloh Emily Phillips Michael H. Reimer Adam J. Wargolet Alison E. Meyer Kirthi Pulakanti Aaron D. Viny Jessica J. Loppnow Ross L. Levine John Anto Pulikkan Nan Zhu Sridhar Rao |
| author_sort |
Katelyn E. Heimbruch |
| title |
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
| title_short |
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
| title_full |
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
| title_fullStr |
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
| title_full_unstemmed |
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
| title_sort |
dot1l inhibitors block abnormal self-renewal induced by cohesin loss |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/4bea0347dc9d49beb5298d2cdd70741f |
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