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Identification of functional cooperative mutations of SETD2 in human acute leukemia.

ABSTRACT: Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.

SUBMITTER: Zhu X

PROVIDER: S-EPMC4440318 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Identification of functional cooperative mutations of SETD2 in human acute leukemia.

Zhu Xiaofan X He Fuhong F Zeng Huimin H Ling Shaoping S Chen Aili A Wang Yaqin Y Yan Xiaomei X Wei Wei W Pang Yakun Y Cheng Hui H Hua Chunlan C Zhang Yue Y Yang Xuejing X Lu Xin X Cao Lihua L Hao Lingtong L Dong Lili L Zou Wei W Wu Jun J Li Xia X Zheng Si S Yan Jin J Zhou Jing J Zhang Lixia L Mi Shuangli S Wang Xiaojuan X Zhang Li L Zou Yao Y Chen Yumei Y Geng Zhe Z Wang Jianmin J Zhou Jianfeng J Liu Xin X Wang Jianxiang J Yuan Weiping W Huang Gang G Cheng Tao T Wang Qian-Fei QF

Nature genetics 20140209 3

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were ...[more]

PMID: 24509477

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Project description:BackgroundHeterogeneity of leukemia-initiating cells (LICs) is a major obstacle in acute myeloid leukemia (AML) therapy. Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML. However, the functional heterogeneity including the drug response of coexistent LICs remains unclear. Therefore, this study aimed to clarify the intra-heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments.MethodsSpleen cells from the primary Setd2-/- -AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model. Flow cytometry was used to analyze the immunophenotype of the leukemic mice. Whole-genome sequencing was conducted to detect secondary hits responsible for leukemia transformation. A serial transplantation assay was used to determine the self-renewal potential of Setd2-/- -AML cells. A limiting-dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells. Bulk and single-cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs. Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs.ResultsIn this study, we observed an aged Setd2-/- mouse developing AML with co-mutation of NrasG12S and BrafK520E . Further investigation identified two types of LICs residing in the c-Kit+ B220+ Mac-1- and c-Kit+ B220+ Mac-1+ subsets, respectively. In vivo transplantation assay disclosed the heterogeneity in differentiation between the coexistent LICs. Besides, an intrinsic doxorubicin-resistant transcriptional signature was uncovered in c-Kit+ B220+ Mac-1+ cells. Indeed, doxorubicin plus cytarabine (DA), the standard chemotherapeutic regimen used in AML treatment, could specifically kill c-Kit+ B220+ Mac-1- cells, but it hardly affected c-Kit+ B220+ Mac-1+ cells. Transcriptome analysis unveiled a higher activation of RAS downstream signaling pathways in c-Kit+ B220+ Mac-1+ cells than in c-Kit+ B220+ Mac-1- cells. Combined treatment with DA and RAS pathway inhibitors killed both c-Kit+ B220+ Mac-1- and c-Kit+ B220+ Mac-1+ cells and attenuated disease progression.ConclusionsThis study identified two cell subsets enriched for LICs in murine Setd2-/- -AML and disclosed the transcriptional and functional heterogeneity of LICs, revealing that the coexistence of different types of LICs in this model brings about diverse drug response.

Dataset Information

Identification of functional cooperative mutations of SETD2 in human acute leukemia.

Publications

Identification of functional cooperative mutations of SETD2 in human acute leukemia.

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