Title

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

UMMS Affiliation

Division of Hematology Oncology, Department of Medicine

Publication Date

2021-07-08

Document Type

Article

Disciplines

Cancer Biology | Hematology | Hemic and Lymphatic Diseases | Neoplasms | Oncology

Abstract

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.

Keywords

Myeloid Neoplasia, bcl2 gene, bcl-2 protein, leukemia, leukemia, myeloid, mice, rna, rna, messenger, rna-binding proteins, cell survival, apoptosis

DOI of Published Version

10.1182/blood.2020009676

Source

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 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner. Blood. 2021 Jul 8;138(1):71-85. doi: 10.1182/blood.2020009676. PMID: 33763698; PMCID: PMC8667054. Link to article on publisher's site

Journal/Book/Conference Title

Blood

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33763698

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