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Homo sapiens
69 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.
Publication Title
Gefitinib induces myeloid differentiation of acute myeloid leukemia.
Sample Metadata Fields
Disease, Disease stage, Cell line
View Samples
GSE15648- Homo sapiens
- 30 Downloadable Samples
Affymetrix Human Genome U95A Array (hgu95a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Identification of AML1-ETO modulators by chemical genomics.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 30 Downloadable Samples
- Affymetrix Human Genome U95A Array (hgu95a)
Description
Somatic rearrangements of transcription factors are common abnormalities in the acute leukemias. With rare exception, however, the resultant protein products have remained largely intractable as pharmacologic targets. One example is AML1-ETO, the most common translocation reported in acute myeloid leukemia (AML). To identify AML1-ETO modulators, we screened a small molecule library using a chemical genomic approach. Gene expression signatures were used as surrogates for the expression versus loss of the translocation in AML1-ETO-expressing cells. The top classes of compounds that scored in this screen were corticosteroids and dihydrofolate reductase (DHFR) inhibitors. In addition to modulating the AML1-ETO signature, both classes induced evidence of differentiation, dramatically inhibited cell viability, and ultimately induced apoptosis via on-target activity. Furthermore, AML1-ETO-expressing cell lines were exquisitely sensitive to the effects of corticosteroids on cellular viability compared with nonexpressers. The corticosteroids diminished AML1-ETO protein in AML cells in a proteasome- and glucocorticoid receptor-dependent manner. Moreover, these molecule classes demonstrated synergy in combination with standard AML chemotherapy agents and activity in an orthotopic model of AML1-ETO-positive AML. This work suggests a role for DHFR inhibitors and corticosteroids in treating patients with AML1-ETO-positive disease.
Publication Title
Identification of AML1-ETO modulators by chemical genomics.
Sample Metadata Fields
Disease, Disease stage, Cell line
View Samples GSE15647- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U95A Array (hgu95a)
Description
U937 AML cells that express an inducible AML1-ETO construct under the control of the tetracycline promoter.
Publication Title
Identification of AML1-ETO modulators by chemical genomics.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Genome U95A Array (hgu95a)
Description
Kasumi-1 AML cells that were transfected in triplicate with AML1-ETO or luciferase siRNA constructs by either Amaxa nucleofection or Biorad siLentFect and incubated for 96 hours.
Publication Title
Identification of AML1-ETO modulators by chemical genomics.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 21 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.
Publication Title
SYK is a critical regulator of FLT3 in acute myeloid leukemia.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 44 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6).
Publication Title
The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a), Affymetrix HT Human Genome U133A Array (hthgu133a)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix HT Human Genome U133A Array (hthgu133a), Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene expression profiling was performed on primary human erythroid progenitor cells expressing a control shRNA (luciferase), two different HDAC1 shRNAs, and two different HDAC2 shRNAs.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Gene expression profiling was performed on primary human erythroid progenitor cells left untreated or treated with 2uM NK57 for 3 days.
Publication Title
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Sample Metadata Fields
Specimen part, Treatment
View Samples