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Gene expression in TAL1-driven T-cell ALL in response to TAL1-KD, UTX-KD, and GSKJ4 treatment

ABSTRACT: T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and as such T-ALL treatments are uniformly applied across subtypes leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL whereby a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in dosage and activity of the histone 3 lysine 27 (H3K27) demethylase UTX. Specifically, we identify UTX as a co-activator of TAL1. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a potent oncogene essential for maintaining the leukemic phenotype of TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we designed a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that is highly effective against TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72299 | GEO | 2016/02/01

SECONDARY ACCESSION(S): PRJNA293697

REPOSITORIES: GEO

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H3K27 methylation changes in Jurkat cells in response to TAL1-KD

Project description:T-cell Acute Lymphoblastic Leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and as such T-ALL treatments are uniformly applied across subtypes leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL whereby a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in dosage and activity of the histone 3 lysine 27 (H3K27) demethylase UTX. Specifically, we identify UTX as a co-activator of TAL1. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a potent oncogene essential for maintaining the leukemic phenotype of TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we designed a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that is highly effective against TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.

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T-cell ALL in response to TAL1-KD, UTX-KD, and GSKJ4 treatment

Project description:T-cell ALL in response to TAL1-KD, UTX-KD, and GSKJ4 treatment

| PRJNA293693 | ENA

The H3K27 demethylase Utx facilitates somatic and germ cell epigenetic reprogramming to pluripotency [Affymetrix gene expression]

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