Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling1. In this study we report the presence of loss-of-function mutations and deletions of EZH2 and SUZ12 genes, encoding critical components of the Polycomb Repressive Complex 2 (PRC2) complex2,3, in 25% of T-ALLs. To further study the role of the PRC2 complex in T-ALL, we used NOTCH1-induced animal models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark lysine-27 tri-methylation of histone 3 (H3K27me3)4 by antagonizing the activity of the Polycomb Repressive Complex 2 (PRC2) complex. These studies demonstrate a tumor suppressor role for the PRC2 complex in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

“…26 EZH2, located on 7q36.1, has been shown to be mutated in myeloid malignancies and portends high-risk disease. [27][28][29] MLL5, located on 7q22.1, has been known to play a role in cell differentiation and self-renewal. [30][31][32] In our cohort, all cases had at least one commonly deleted region deleted.…”

“…Of the 10 patients with mild dyspoiesis, 7 (patients 15,[19][20][21][22][23][24] showed a variable degree of cytopenia and 3 (patients 13, 14, 25) had normal complete blood cell counts. Of the 16 patients who showed no evidence of dysplasia, 6 (cases [16][17][18][26][27][28] demonstrated mild cytopenia and the other 10 patients (cases 29-38) had normal complete blood cell counts (Figure 1). Patient 39 showed marked leukocytosis in the setting of active T-PLL.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…77 Moreover, somatic mutations and deletions of EZH2 were also identified in malignancies. [79][80][81][82] In particular, T cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy in which H3K27 methylation is reduced by a loss-of-function EZH2 mutation. 81,82 Mutations resulting in the replacement of a single tyrosine in the SET domain of the EZH2 protein (tyrosine Y641) can occur in diffuse large B-cell lymphomas and follicular lymphomas and reduce enzyme activity.…”

“…Mutations have been reported in the genes encoding KDM5A (JARID1A); KDM5C (JARID1C), which affects H3K4 methylation; and KDM6A (UTX), which affects H3K27 methylation. 50,81,82,98,105,106 UTX (KDM6A) and JMJD3 (KDM6B) Besides EZH2 methyltransferase, H3K27 methylation is also determined by the activity of demethylases, including UTX/ KDM6A and JMJD3/KDM6B. Somatic loss-of-function mutations of UTX are found in multiple myeloma, esophageal squamous cell carcinomas, renal carcinomas, and occasionally in breast cancer, AML, T-ALL, GBM, and colorectal and bladder cancer (Table 1) (for review see.…”

“…Somatic loss-of-function mutations of UTX are found in multiple myeloma, esophageal squamous cell carcinomas, renal carcinomas, and occasionally in breast cancer, AML, T-ALL, GBM, and colorectal and bladder cancer (Table 1) (for review see. 70,81,82 ), suggestive of a tumor suppressor role for UTX. Both JMJD3 and UTX function as part of a transcriptional activator complex that includes the MLL3/MLL4 H3K4 methyltransferases, indicating that these enzymes have a dual role involving removal of H3K27 methyl marks and addition of methyl groups to H3K4 (reviewed in 76 ).…”