Genome-wide comparison of AML leukemic stem cells (LSCs) and normal human hematopoietic stem cells (HSCs).
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Yoshikane Kikushige
PROVIDER: E-GEOD-24395 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Gene expression analysis of AML LSCs vs normal HSCs
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Project description:The cyclin-dependent kinases (CDK) CDK6 and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (HSCs and LSCs) that exceeds its function as cell-cycle regulator. Although hematopoiesis appears regular under steady state conditions Cdk6-/- HSCs do not efficiently repopulate upon competitive transplantation and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil (5-FU) treatment. We find that activation of HSCs requires CDK6, which interferes with transcription of key regulators including Egr1. The central role of Egr1 is supported by transcriptional profiling of HSCs. The impaired repopulation capacity extends to BCR-ABLp210+ leukemic stem cells. Transplantation with BCR-ABLp210+-infected bone marrow (BM) from Cdk6-/- mice fails to induce disease although recipient mice do harbor LSCs. Egr1 knock-down in cdk6-/- BCR-ABLp210+ LSKs significantly enhances colony formation underlining the importance of the Cdk6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and as essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs. Four-condition experiment, Untreated or polyI:C-treated CDK6-/- cells versus untreated or polyI:C-treated wild-type cells. Biological replicates: 3 untreated replicates, 3 polyI:C-treated replicates.
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Project description:Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. We found that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification was associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cell (HSC) function and AML, such as HoxA cluster genes. In vivo, HMGN1 overexpression was linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperated with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieved the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.
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Project description:High expression of CDK7, a cell cycle regulator and transcriptional modulator, correlates with poor outcomes in acute myeloid leukemia (AML). We report that TGN-1062, a novel CDK7 inhibitor, exhibits significant antileukemic effects by inhibiting cell growth and inducing apoptosis in AML cell lines and primary CD34+CD38- blasts (enriched for leukemia stem cells; LSCs), while sparing normal CD34+CD38- cells (enriched for hematopoietic stem cells; HSCs). Our study revealed that TGN-1062 treatment in primary CD34+CD38- AML blasts suppress RNA m6A modification by downregulating METTL3/14 proteins, key components of the m6A methyltransferase complex that regulate RNA stability and translation. Decrease in METTL proteins reduced BCL-2 m6A RNA modification and led to increased BCL-2 mRNA decay and protein levels. BCL-2 downregulation resulted in disruption of mitochondrial metabolism and mitofusion in LSCs through decrease of HMGB1/HSPB1 and NRF2/DRP1 signaling, respectively. In vivo, TGN-1062 significantly reduced leukemia burden and prolonged survival in a murine MllPTD/WT/Flt3ITD/ITD AML model and in FLT3-WT and inv(16) AML patient-derived xenografts (PDXs). Increased survival in secondary transplant experiments supported TGN-1062 activity on LSCs. Of note, we proved that TGN-1062 synergized with the BCL-2 inhibitor, venetoclax in eliminating LSCs in both murine and PDX AML models, underscoring its potential as a promising therapeutic approach for AML patients.
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Project description:The cyclin-dependent kinases (CDK) CDK6 and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (HSCs and LSCs) that exceeds its function as cell-cycle regulator. Although hematopoiesis appears regular under steady state conditions Cdk6-/- HSCs do not efficiently repopulate upon competitive transplantation and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil (5-FU) treatment. We find that activation of HSCs requires CDK6, which interferes with transcription of key regulators including Egr1. The central role of Egr1 is supported by transcriptional profiling of HSCs. The impaired repopulation capacity extends to BCR-ABLp210+ leukemic stem cells. Transplantation with BCR-ABLp210+-infected bone marrow (BM) from Cdk6-/- mice fails to induce disease although recipient mice do harbor LSCs. Egr1 knock-down in cdk6-/- BCR-ABLp210+ LSKs significantly enhances colony formation underlining the importance of the Cdk6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and as essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
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