Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness.
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ABSTRACT:
PROVIDER: EGAC00001001054 | EGA |
REPOSITORIES: EGA
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Project description:Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.
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Project description:Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat de novo and secondary acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. We performed a comprehensive analysis of 16 histone H3 genes in 434 primary acute myeloid leukemia (AML) samples and identified mutations in adult and pediatric cases (1.6%), with a higher incidence in secondary AML (s-AML) (9%). These included four novel amino acid substitutions (Q69H, A26P, R2Q and R8H) as well as K27M and K27I in H3.1 and H3.3 genes. These mutations are important early events in leukemogenesis as they were observed in pre-leukemic HSCs in two cases and were in the major clones in every sample. Consistent with a role in pre-leukemic HSC clonal expansion, the mutant histones increased functional human HSC frequency and altered differentiation along the erythroid and myeloid lineages, with activity dependent on the specific mutation (K27M, K27I and Q69H). In established human leukemia, the K27M/I mutant histones amplified leukemic aggressiveness, with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. This was associated with increased expression in genes involved in erythrocyte and myeloid differentiation, correlated with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. While histone mutations can co-occur with alterations in RUNX1, we observed that the functional impact of histone mutations is independent of RUNX1 mutations. Taken together, these data establish the involvement of H3 mutations as early drivers of pre-leukemic HSC expansion and leukemogenesis.
2019-04-05 | GSE122273 | GEO
Project description:Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. Comprehensive analysis of 16 histone H3 genes in 434 primary AML samples identified Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), and a higher incidence in secondary AML (s-AML) (9%). We establish that these mutations are important early events in leukemogenesis. They occur in pre-leukemic HSCs, increase the frequency of functional human HSCs, and alter differentiation. The mutations are present in the major leukemic clones in primary samples, and the mutant histones amplify leukemic aggressiveness with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. These effects are dependent on the specific mutation. Genome-wide analysis of K27 mutants revealed increased expression of genes involved in erythrocyte and myeloid differentiation with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutations, although they can co-occur. These data establish the involvement of H3 mutations as initial drivers of pre-cancerous stem cell expansion and leukemogenesis.
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Project description:Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness
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Project description:The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here, we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 3.88-fold increase in cell number. These cultured CD34+ cells repopulated recipient mice for 21 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of the JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.
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Project description:Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ~5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of the BCL11A+58 enhancer, overcoming a major obstacle to ex vivo gene correction for human hemoglobinopathies.
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Project description:Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy. LGC006, a less potent SR1 analog, was also examined. KEYWORDS: two compounds, multiple doses, one time point two compounds, multiple doses, one time point
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