YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

Feng M ，Xie X ，Han G ，Zhang T ，Li Y ，Li Y ，Yin R ，Wang Q ，Zhang T ，Wang P ，Hu J ，Cheng Y ，Gao Z ，Wang J ，Chang J ，Cui M ，Gao K ，Chai J ，Liu W ，Guo C ，Li S ，Liu L ，Zhou F ，Chen J ，Zhang H ... -  《-》

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

Persistence of malignant clones 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. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.

Perner F ，Schnoeder TM ，Xiong Y ，Jayavelu AK ，Mashamba N ，Santamaria NT ，Huber N ，Todorova K ，Hatton C ，Perner B ，Eifert T ，Murphy C ，Hartmann M ，Hoell JI ，Schröder N ，Brandt S ，Hochhaus A ，Mertens PR ，Mann M ，Armstrong SA ，Mandinova A ，Heidel FH ... -  《-》

The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability.

N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.

Zhang N ，Shen Y ，Li H ，Chen Y ，Zhang P ，Lou S ，Deng J ... -  《-》

METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification.

N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here, we report that METTL14, a key component of the m6A methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21) and is downregulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells and inhibits AML cell survival/proliferation. METTL14 is required for development and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through m6A modification, while the protein itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis and highlight the critical roles of METTL14 and m6A modification in normal and malignant hematopoiesis.

Weng H ，Huang H ，Wu H ，Qin X ，Zhao BS ，Dong L ，Shi H ，Skibbe J ，Shen C ，Hu C ，Sheng Y ，Wang Y ，Wunderlich M ，Zhang B ，Dore LC ，Su R ，Deng X ，Ferchen K ，Li C ，Sun M ，Lu Z ，Jiang X ，Marcucci G ，Mulloy JC ，Yang J ，Qian Z ，Wei M ，He C ，Chen J ... -  《-》

YBX1 regulates the survival of chronic myeloid leukemia stem cells by modulating m(6)A-mediated YWHAZ stability.

Chronic myeloid leukemia (CML) is a myeloproliferative disease derived from hematopoietic stem cells (HSCs) that harbor Philadelphia chromosome (Ph chromosome). In clinic, leukemia stem cells (LSCs) in CML are insensitive to the treatment with tyrosine kinase inhibitors, and are responsible for disease relapse. However, the molecular mechanisms for maintaining LSCs survival remain elusive. CML patient-derived cell lines and BCR-ABL-induced CML mouse model were used to explore the role of YBX1 in regulating the survival of CML LSCs. Bone marrow transduction and transplantation, and colony-forming unit assay were used to investigate LSC function. The underlying mechanism of how YBX1 regulates LSCs survival were assessed using flow cytometry, RNA sequencing, western blot, RNA decay assay, co-immunoprecipitation and RNA immunoprecipitation. Here we show that RNA-binding protein YBX1 plays an important role in regulating survival of CML LSCs. We find that YBX1 expression is significantly increased in CML cells, and confirm that YBX1 is required for maintaining survival of LSCs. Deletion of YBX1 impairs the propagation of CML through blocking cell proliferation and inducing apoptosis of LSCs. Mechanistically, we find that YBX1 regulates expression of apoptotic associated genes. YBX1 cooperates with RNA m6A reader IGF2BPs to stabilize YWHAZ transcript in an m6A-dependent manner, and loss of YBX1 decreases YWHAZ expression by accelerating mRNA decay. Restoration of YWHAZ efficiently rescues the defects of YBX1-deficient CML cells. Our findings reveal a critical role of YBX1 in maintaining survival of CML LSCs, which provides a rationale for targeting YBX1 in CML treatment.

Chai J ，Wang Q ，Qiu Q ，Han G ，Chen Y ，Li W ，Zhang H ... -  《-》