A novel fusion protein TBLR1-RAR\u03b1 acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies

Shouyun Li,Yingxi Xu,Xue Yang,Qing Rao,Zheng Tian,Min Wang,Haiyan Xing,Yirui Chen,Shuang Liu,Jianxiang Wang,Kejing Tang

doi:10.1038/s41419-021-03889-0

Abstract

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and its fusion partners. For decades, the advent of all-trans retinoic acid (ATRA) synergized with arsenic trioxide (As2O3) has turned most APL from highly fatal to highly curable. TBLR1-RARα (TR) is the tenth fusion gene of APL identified in our previous study, with its oncogenic role in the pathogenesis of APL not wholly unraveled. In this study, we found the expression of TR in mouse hematopoietic progenitors induces blockade of differentiation with enhanced proliferative capacity in vitro. A novel murine transplantable leukemia model was then established by expressing TR fusion gene in lineage-negative bone marrow mononuclear cells. Characteristics of primary TR mice revealed a rapid onset of aggressive leukemia with bleeding diathesis, which recapitulates human APL more accurately than other models. Despite the in vitro sensitivity to ATRA-induced cell differentiation, neither ATRA monotherapy nor combination with As2O3 confers survival benefit to TR mice, consistent with poor clinical outcome of APL patients with TR fusion gene. Based on histone deacetylation phenotypes implied by bioinformatic analysis, HDAC inhibitors demonstrated significant survival superiority in the survival of TR mice, yielding insights into clinical efficacy against rare types of APL.

Highlights

Acute promyelocytic leukemia (APL) is a distinct hematopoietic malignancy accounting for ~10–15% of acute myeloid leukemia (AML) cases [1]
DISCUSSION the paradigmatic combined therapy of all-trans retinoic acid (ATRA) and As2O3 have benefited most patients with APL to be definitively cured, rare cases of APL with fusion genes other than PML-RARα still exist with molecular pathogenesis remaining largely unclear
Previous studies have utilized multiple mouse models with regulatory sequences to direct the expression of PML-RARα under promoters of specific stages (CTSG and MRP8), contributing to antecedent myeloproliferative diseases (MPD) after a long latent period with high white blood cell (WBC) counts and different penetrance [14, 15, 18, 20, 27]

Summary

Introduction

Acute promyelocytic leukemia (APL) is a distinct hematopoietic malignancy accounting for ~10–15% of acute myeloid leukemia (AML) cases [1]. Rare RARα partner genes other than PML have been reported, including PLZF [3], NPM1 [4], NuMA [5], STAT5b [6], PRKAR1A [7], FIP1L1 [8], BCOR [9], OBFC2A [10], TBLR1 [11], GTF2I [12], and FNDC3B [13] Among these X-RARα fusion genes, TBLR1RARα (TR) was the tenth RARα chimera identified in our previous study from three cases of APL with t(3;17) chromosomal translocation [11]. What is the role of TR in leukemogenesis? Would it interfere with the differentiation and proliferative capacity of hematopoietic stem/progenitor cells (HSPCs)? Due to a rarity of clinical cases, preclinical mouse modeling of APL with rare fusion genes may help to lay the groundwork for unraveling the molecular basis of potential treatment toward the disease cure

Methods

Results

Conclusion