Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE34726 | GEO | 2012/03/14
SECONDARY ACCESSION(S): PRJNA150425
REPOSITORIES: GEO
Similar Datasets
Project description:Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non-APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine-specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4(me2)) across the genome, but it did increase H3K4(me2) and expression of myeloid-differentiation-associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID ? (with interleukin-2 (IL-2) receptor ? chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.
| S-EPMC3539284 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE34672: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [Illumina HumanHT-12 gene expression array] GSE34725: Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [ChIP-Seq] Refer to individual Series
2012-03-14 | E-GEOD-34726 | biostudies-arrayexpress
Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. ChIP-seq was used to study the effects of ATRA, TCP and ATRA/TCP treatment on H3K4 dimethylation. In addition to the three treatment samples, two reference samples were processed: (i) An untreated sample using the same anti-H3K4me2 antibody and an untreated sample using IgG. These five sequencing experiments were conducted using HL-60 cells and TEX cells, leading to 10 ChIP-seq samples in total.
2012-03-14 | E-GEOD-34725 | biostudies-arrayexpress
Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML.
2012-03-14 | GSE34725 | GEO
Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. Overall, 30 specimens derived from HL-60 or TEX cell line were treated with drugs and hybridized to Illumina HumanHT-12 gene expression arrays.
2012-03-14 | E-GEOD-34672 | biostudies-arrayexpress
Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML.
2012-03-14 | GSE34672 | GEO
Project description:Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia
| PRJNA150425 | ENA
Project description:The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.
| S-EPMC7141832 | biostudies-literature
Project description:Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to ?-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.
| S-EPMC3824007 | biostudies-other
Project description:PurposeIn preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).Patients and methodsSeventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).ResultsATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.ConclusionsThese data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
| S-EPMC8026558 | biostudies-literature