Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis

Cai, Zhigang; Kotzin, Jonathan J.; Ramdas, Baskar; Chen, Sisi; Nelanuthala, Sai; Palam, Lakshmi Reddy; Pandey, Ramesh C.; Mali, Raghuveer Singh; Liu, Yan; Kelley, Mark R.; Sandusky, George E.; Mohseni, Morvarid; Williams, Adam; Henao‐Mejia, Jorge; Kapur, Reuben

doi:10.1016/j.stem.2018.10.013

Cited by 249 publications

(230 citation statements)

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“…While we have identified a stem cell intrinsic mechanism by which mutant p53 drives clonal hematopoiesis, recent studies indicate that mutations identified in CHIP may utilize cell extrinsic mechanisms to promote clonal hematopoiesis 51–52 . For example, mutant hematopoietic cells displayed increased secretion of pro-inflammatory cytokines such as IL-1β and IL-6 51–52 . Since some inflammatory response genes are upregulated in p53 mutant HSPCs (data not shown), we will investigate the cell extrinsic mechanisms by which mutant p53 drives CHIP in the future.…”

Section: Discussionmentioning

confidence: 85%

Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

Chen

Wang

et al. 2019

Preprint

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24Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated 25 with increased risks of hematological malignancies. While TP53 mutations have been 26 identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic 27 stem and progenitor cell (HSPC) expansion are largely unknown. We discovered that mutant 28 p53 confers a competitive advantage to HSPCs following transplantation and promotes 29 HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with 30 EZH2 and enhances its association with the chromatin, thereby increasing the levels of 31 H3K27me3 in genes regulating HSPC self-renewal and differentiation. Further, genetic and 32 pharmacological inhibition of EZH2 decrease the repopulating potential of p53 mutant 33HSPCs. Thus, we have uncovered an epigenetic mechanism by which mutant p53 drives 34 clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel 35 therapeutic target for preventing CHIP progression and treating hematological malignancies 36 with TP53 mutations. 37 38 39 40 4 Clonal hematopoiesis of indeterminate potential (CHIP), also known as age-related clonal 41 hematopoiesis (ARCH), occurs when a single mutant hematopoietic stem and progenitor cell 42 (HSPC) contributes to a significant clonal proportion of mature blood lineages during aging 1-43 3 . CHIP is common in aged healthy individuals and associated with increased risks of de 44 novo and therapy-related hematological neoplasms, including myelodysplastic syndromes 45 (MDS) and acute myeloid leukemia (AML) 4-8 . CHIP is also associated with increased all-46 cause mortality and risk of cardio-metabolic disease [4][5][6] 9 . While these findings suggest that 47 mutations identified in CHIP likely drive disease development, mechanisms by which these 48 mutations promote HSPC expansion are largely unknown [4][5][6][7][8][9] . 49Most individuals with CHIP carry hematological malignancy-associated mutations, 50including DNMT3A, TET2, ASXL1, JAK2, and TP53 4-6 . The TP53 gene, which encodes the 51 tumor suppressor protein p53, ranks in the top five among genes that were mutated in CHIP 52 4-6, 10-12 . p53 bears the usual hallmarks of a transcription factor, with an amino-terminal 53 transactivation domain (TAD), a core DNA-binding domain (DBD) and carboxy-terminal 54 tetramerization (TET) and regulatory domains (REG) [13][14] . It regulates a large number of 55 genes in response to a variety of cellular insults, including oncogene activation, DNA 56 damage, and inflammation, to suppress tumorigenesis [13][14] . TP53 mutations and deletions 57 were found in approximately half of all human cancers, including hematological malignancies 58 [13][14] . Recently, somatic TP53 mutations were identified in CHIP 4-6 . TP53 mutations were 59 also commonly found in therapy-related CHIP 10, 12 . Interestingly, some individuals with Li-60Fraumeni syndrome (LFS), who carry germline TP53 mutations, develop MDS and AML as 61 they age [14][15] . I...

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Section: Discussionmentioning

confidence: 85%

Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

Chen

Wang

et al. 2019

Preprint

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“…51 On a functional level, reduced TET2 expression leads to clonal expansion of HSCs, [52][53][54] particularly in response to inflammatory stress. 55 ASXL1, another recurrently mutated gene in CH, also encodes a protein linked to epigenetic modification. Unlike DNMT3A and TET2 that directly modify DNA, ASXL1 is part of the so-called polycomb-group complex, which regulates transcription via histone modification.…”

Section: Functional Implications Of Recurrent Gene Mutations In Chmentioning

confidence: 99%

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Hartmann

Metzeler

2019

Genes Chromosomes & Cancer

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Myeloid neoplasms including myelodysplastic syndromes and acute myeloid leukemia (AML) originate from hematopoietic stem cells through sequential acquisition of genetic and epigenetic alterations that ultimately cause the disease‐specific phenotype of impaired differentiation and increased proliferation. It has become clear that preleukemic clonal hematopoiesis (CH), characterized by an expansion of stem and progenitor cells that carry somatic mutations but are still capable of normal differentiation, can precede the development of clinically overt myeloid neoplasia by many years. CH commonly develops in the aging hematopoietic system, yet progression to myelodysplasia or AML is rare. The discovery that myeloid neoplasms frequently develop from premalignant precursor conditions that are detectable in many healthy individuals has important consequences for the diagnosis, and potentially for the treatment of these disorders. In this review, we summarize the current knowledge on CH as a precursor of myeloid cancers and the implications of CH‐related gene mutations in the diagnostic workup of patients with suspected myelodysplastic syndrome. We will discuss the risk of progression associated with CH in healthy persons and in patients undergoing chemotherapy for a non‐hematologic cancer, and the significance of CH in autologous and allogeneic stem cell transplantation. Finally, we will review the significance of preleukemic clones in AML and their persistence in patients who achieve a remission after chemotherapeutic treatment.

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“…There is growing evidence of context-specific expansion of oncogenically-initiated hematopoietic progenitors: BCR-ABL or Ppm1d-deficiency with chemotherapy (Bilousova et al, 2005;Hsu et al, 2018;Kahn et al, 2018); Notch activation, Tp53-deficiency, or Cebpa-deficiency following γ-irradiation (Bondar and Medzhitov, 2010;Fleenor et al, 2015b;Marusyk et al, 2009;Marusyk et al, 2010); BCR-ABL, Myc, NRas V12 , or AML1-ETO in aging (Henry et al, 2015;Henry et al, 2010;Vas et al, 2012); and Jak V617F with TNF-α exposure (Fleischman et al, 2011) or Tet2-knockout with LPS challenge (Cai et al, 2018). Here, we show that chronic IL-1β is sufficient to drive selective expansion of Cebpa-deficient MPPs, directly connecting an inflammatory signaling pathway to a transcriptional fate network.…”

Section: Strikingly Chronic Il-1β Exposure Triggered a Fitness Advanmentioning

confidence: 99%

Chronic Interleukin-1 exposure triggers selective expansion of Cebpa-deficient multipotent hematopoietic progenitors

Higa

2020

Preprint

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The early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1β (IL-1β), impacts Cebpadeficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found that Cebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection for Cebpa loss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1β, and competitively expand. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.

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Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis

Cited by 249 publications

References 65 publications

Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

Chronic Interleukin-1 exposure triggers selective expansion of Cebpa-deficient multipotent hematopoietic progenitors

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