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ABT-737 treatment induces regulation and activation of pathways implicated in cell survival, proliferation and stem cells in treated AML mice survival, proliferation and stem cells in treated AML mice

ABSTRACT: Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 (BH3) mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with treated cells compared with cells from untreated mice, with a reduction of bone marrow (BM) blasts, LSK and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by Tc-99m-labeled Annexin V single photon emission computed tomography (SPECT) and ex vivo by Annexin V/7AAD flow cytometry, TUNEL, caspase 3 cleavage and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type AKT, ERK1/2 and MEK patterns in spleen cells after treatment, which show reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE48601 | GEO | 2013/11/06

SECONDARY ACCESSION(S): PRJNA210786

REPOSITORIES: GEO

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ABT-737 treatment induces regulation and activation of pathways implicated in cell survival, proliferation and stem cells in treated AML mice survival, proliferation and stem cells in treated AML mice

Project description:Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 (BH3) mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with treated cells compared with cells from untreated mice, with a reduction of bone marrow (BM) blasts, LSK and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by Tc-99m-labeled Annexin V single photon emission computed tomography (SPECT) and ex vivo by Annexin V/7AAD flow cytometry, TUNEL, caspase 3 cleavage and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type AKT, ERK1/2 and MEK patterns in spleen cells after treatment, which show reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells. NRASD12/BCL-2 double transgenic mice were analysed by enriching for primitive Sca1+ cells from splenocytes from untreated and ABT-737 treated mice. RNA was extracted analysed for gene expression profiles using exon specific arrays.

2013-11-06 | E-GEOD-48601 | biostudies-arrayexpress

Genome-wide DNA methylation in MDS/secondary AML and de novo AML

Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling Direct comparison of DNA methylation in bone marrow samples from patients with Myelodysplastic syndrome or secondary Acute Myeloid Leukemia (AML) at baseline and after in vivo treatment with 5-azacytidine + etinostat. A comparison to de novo normal karyotype AML was also performed. Two control groups were included: one consisting of 8 CD34+ bone marrow samples from healthy donors and a second one consisting of matched CD34+ and CD34- fractions from the bone marrows of 4 healthy donors.

2010-05-15 | E-GEOD-17328 | biostudies-arrayexpress

Human AML secretome and correlation with Anti-Apoptotic Index, part 1

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. Herein, we further explored this aspect of apoptosis in AML. Firstly, the intra-individual ex vivo apoptosis-related profiles of normal lymphocytes and AML blasts showed a strong correlation, with expression values far beyond control lymphocytes. Secondly, we demonstrated that apoptosis-resistant primary AML blasts, as opposed to apoptosis-sensitive cells, were able to up-regulate BCL-2 expression in sensitive AML blasts in contact cultures (p=0.0067 and p=1.0 respectively). Using proteomics we further set out to identify novel proteins possibly engaged in apoptosis regulation. Proteomics analysis revealed that major functional protein clusters upregulated in secretomes of apoptosis-resistant AML, were presumably engaged in global gene regulation including mRNA splicing, protein translation and chromatin remodeling.

2016-02-03 | PXD001476 | Pride

Genome-Wide CRISPR-Cas9 Screening Identifies a Synergy between Hypomethylating Agents and SUMOylation Blockade in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Project description:Hypomethylating agents (HMAs) are frontline therapies effective at altering the natural course of Myelodysplastic Neoplasms (MDS). However, acquired resistance and treatment failure are hallmarks of HMA therapy. Developing effective and rational HMA-focused combinatorial therapies is challenging as the underlying mechanisms driving HMA efficacy are complex. To address this clinical need, we performed a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and characterized TOPORS as a highly ranked target that synergizes with HMAs to reduce leukemic burden and improve survival in xenograft models. We demonstrated that the depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. Importantly, the combination of HMAs with targeting of TOPORS did not functionally impair healthy hematopoiesis. While inhibitors of TOPORS are currently unavailable, we show that inhibition of SUMOylation (upstream of TOPORS functions) with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with the inhibition of SUMOylation demonstrates a favourable therapeutic index and represents a rational framework towards the treatment of High-Risk MDS (HR-MDS) or Acute Myeloid Leukemia (AML).

2024-07-25 | PXD050539 | Pride

Acquired TET2 mutation-linked clonal hematopoiesis in FPD/AML patient led to the development of pre-leukemic clone resulting independently in T2-ALL and AML-M0

Project description:Germline RUNX1 mutations are found in familial platelet disorders with predisposition to acute myelogenous leukemia (FPD/AML). This very rare disease is characterized by thrombocytopenia, platelet dysfunction and a 35% lifetime risk of developing MDS/AML and in rare cases also T-ALL. Here, we focus on a case of a man with a familial history of RUNX1 R174Q mutation who developed at the age of 42 years an EGIL T2-ALL and, two years after remission, an AML-M0. To investigate whether initial and relapsed leukemic blasts originated from the same clone, we performed CGH array and WES on both blasts populations. In both T2-ALL and AML-M0 samples, CGH array revealed loss of 1p36.32-23 and 17q11.2 and nine other small deletions. Both AML-M0 and T2-ALL blasts demonstrated clonal rearrangements of both TCRÎ³ (VÎ³9-JÎ³1-1) and TCRÎ´ (DÎ´2-JÎ´1 and DÎ´2-JÎ´3). 18 genes were found by WES to be mutated in both blasts at a frequency of more than 40%. Additional variants were identified only in T2-ALL or in AML-M0 evoking the existence of a common original clone, which gave rise to subclonal populations. MiSeq technology performed on peripheral blood-derived CD34+ cells five years prior T2-ALL development revealed only missense TET2 P1962T mutation at a frequency of 1% (which reaches a frequency of 50 % in fully transformed leukemic clone) suggesting that this mutation in association with germline RUNX1 R174Q mutation led to amplification of a hematopoietic clone susceptible to acquire other transforming alterations. Identification of clonal hematopoiesis with acquired mutations at low frequency in hematopoietic progenitors before leukemia development could clearly serve as a marker of pre-leukemic state and be helpful in patient care.

2017-06-29 | E-MTAB-4623 | biostudies-arrayexpress

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 3

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-10-21 | MSV000080268 | MassIVE

Genome-wide DNA methylation in MDS/secondary AML and de novo AML

2009-08-05 | GSE17328 | GEO

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 3

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-02-03 | PXD001487 | Pride

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 4

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. The concentrations of these proteins are combined in the Anti Apoptotic index (AAI). We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-10-21 | MSV000080266 | MassIVE

Human AML secretome and exosomes and correlation with Anti-Apoptotic Index, part 4

Project description:Expression of proteins regulating apoptosis (BCL-2, MCL-1, BCL-X and BAX) in acute myeloid leukemia (AML) blasts at diagnosis have been shown to be associated with disease-free survival. The concentrations of these proteins are combined in the Anti Apoptotic index (AAI). We previously found that the initially high apoptosis-resistance of AML cells decreased after therapy, while regaining high levels at relapse. This suggested a dynamic regulation of apoptosis. We hypothesized that expression of apoptosis-related proteins in AML blasts, and possibly also in bystander cells in the bone marrow, is regulated by extracellular factors present in the AML microenvironment. Tumor cell communication with its microenvironment is emerging as an important determinant playing multiple roles in cancer. Both soluble factors and extracellular vesicles (EVs), most notably exosomes, have been shown to influence cellular processes of malignant and normal cells in the tumor microenvironment. We performed a proteomics analysis of the whole secretome as well as of EVs secreted by AML blasts to pinpoint released protein factors that might mediate apoptosis-resistance.

2016-02-03 | PXD003478 | Pride

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