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YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [RIP-Seq]

ABSTRACT: we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival but is dispensable for normal hematopoiesis. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 significantly induces apoptosis, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency promotes mRNA decay in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159153 | GEO | 2021/04/01

REPOSITORIES: GEO

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YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [SLAM-seq]

Project description:we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival but is dispensable for normal hematopoiesis. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 significantly induces apoptosis, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency promotes mRNA decay in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

2021-04-01 | GSE159152 | GEO

YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [RNA-Seq]

Project description:we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival but is dispensable for normal hematopoiesis. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 significantly induces apoptosis, coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia (AML) cells in vitro and in vivo. Loss of YBX1 does not obviously affect normal hematopoiesis. Mechanistically, YBX1 interacts with IGF2BPs and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival due to YBX1 deletion. Thus, our findings uncover a selective and critical role of YBX1 in maintaining myeloid leukemia survival that might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

2021-04-01 | GSE159178 | GEO

Ybx1 is required for Survival of Leukemia Stem Cells and the Development of Chronic Myeloid Leukemia

Project description:Chronic myeloid leukemia (CML) is a myeloproliferative disorder derived from hematopoietic stem cells (HSCs) that harbor Philadelphia chromosome (Ph chromosome). Leukemia stem cells (LSCs) in CML are insensitive to TKIs treatment, and are responsible for disease relapse. However, the molecular mechanisms for LSCs survival remains elusive. Here we show that YBX1 plays an important role in regulating survival of CML LSCs. We find that YBX1 expression is significantly increased in CML cells. Using CML patient-derived cell lines and a BCR-ABL-induced CML mouse model, we confirm that YBX1 is required for survival maintenance of LSCs. Deletion of YBX1 impairs the propagation of CML through impairing cell cycle and inducing apoptosis of LSCs. Mechanistically, we find that YBX1 regulates expression of apoptosis-related genes, and YBX1 binds MYC and BCL2 transcripts. YBX1 loss decreases expression of MYC and BCL2 by accelerating their mRNA decay. In addition, restoration of MYC and BCL2 efficiently rescue the defects of YBX1-deficient CML cells. Overall, our findings reveal a critical role of YBX1 in maintaining survival of CML LSCs, which may provide a rationale for targeting YBX1 in CML treatment.

2022-03-27 | GSE199304 | GEO

YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner

Project description:YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner

| PRJNA667914 | ENA

YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [RIP-Seq]

Project description:YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [RIP-Seq]

| PRJNA668007 | ENA

YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [SLAM-seq]

Project description:YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [SLAM-seq]

| PRJNA667827 | ENA

YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [RNA-Seq]

Project description:YBX1 is selectively required for maintaining myeloid leukemia cell survival by regulating mRNA stability in an m6A-dependent manner [RNA-Seq]

| PRJNA668008 | ENA

YBX1 mediates translation of oncogenic transcripts to control cell competition in AML [RNA-seq]

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YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

Project description:Persistence of malignant clones following cytotoxic or targeted therapy is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. After discontinuation of treatment, these persistent clones have a competitive advantage and re-establish disease. Therefore, targeting strategies that specifically reduce competitive advantage of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified cold-shock protein and splicing factor YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasia. The role of cold-shock proteins in AML, however, remained so far elusive. Using genetic screening, we identified YBX1 as a relevant functional dependency in AML. Inactivation of YBX1 in vitro and in vivo confirmed its role as an essential driver of leukemia development and maintenance. Here, we identified its ability to bind specific mRNAs, including MYC, and amplify their translation at the ribosomes by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupted this regulatory circuit and displaced a number of oncogenic drivers from polysomes, with subsequent depletion of protein abundance. As a consequence, leukemia cells showed reduced proliferation and were out-competed in vitro and in vivo, while normal cells remained largely unaffected. Collectively, this data establishes YBX1 as a specific dependency and therapeutic target in AML that is essentially required for oncogenic protein expression.

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YBX1 mediates translation of oncogenic transcripts to control cell competition in AML [RNA-seq polysomes]

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