Myeloid translocation gene CBFA2T3 directs a relapse gene program and determines patient-specific outcomes in AML

Abstract

CBFA2T3 is a master transcriptional coregulator in hematopoiesis. In this study, we report novel functions of CBFA2T3 in acute myeloid leukemia (AML) relapse. CBFA2T3 regulates cell-fate genes to establish gene expression signatures associated with leukemia stem cell (LSC) transformation and relapse. Gene set enrichment analysis showed that CBFA2T3 expression marks LSC signatures in primary AML samples. Analysis of paired primary and relapsed samples showed that acquisition of LSC gene signatures involves cell type–specific activation of CBFA2T3 transcription via the NM_005187 promoter by GCN5. Short hairpin RNA–mediated downregulation of CBFA2T3 arrests G1/S cell cycle progression, diminishes LSC gene signatures, and attenuates in vitro and in vivo proliferation of AML cells. We also found that the RUNX1-RUNX1T1 fusion protein transcriptionally represses NM_005187 to confer t(8;21) AML patients a natural resistance to relapse, whereas lacking a similar repression mechanism renders non–core-binding factor AML patients highly susceptible to relapse. These studies show that 2 related primary AML-associated factors, the expression level of CBFA2T3 and the ability of leukemia cells to repress cell type–specific CBFA2T3 gene transcription, play important roles in patient prognosis, providing a paradigm that differential abilities to repress hematopoietic coregulator gene transcription are correlated with patient-specific outcomes in AML.

Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia

“…We demonstrated that one mechanism by which CBFA2T3 and RUNX1 promote leukemogenesis or maintain leukemia is by controlling cell proliferation. Our results are concordant with data from Steinauer et al showing that downregulation of CBFA2T3 arrests G1/S cell cycle progression and attenuates in vitro and in vivo proliferation of acute myeloid leukemia cells [50].…”

“…Our results are concordant with data from Steinauer et al . showing that downregulation of CBFA2T3 arrests G1/S cell cycle progression and attenuates in vitro and in vivo proliferation of acute myeloid leukemia cells [ 50 ].…”

“…Few data are available on CBFA2T3 partners in B-cells, but the literature is richer for other hematopoietic lineages. CBFA2T3 depletion arrests cell cycle progression in acute myeloid leukemia cell lines and CD34 + hematopoietic stem and progenitor cells (HSPC) [ 50 , 56 ]. E-box proteins (E2A/HEB), TAL-1 complexes or GATA1 can be proposed to participate in this proliferation arrest [ 57 , 58 ], in particular in the erythroid lineage [ 16 , 59 ].…”

CTCF, a novel fusion partner of ETO2 in a post-transplant relapsed acute myeloid leukemia patient

“…As a nuclear co-repressor, ETO2 interacts with DNA-binding transcription factors and recruits a range of corepressors to inhibit downstream gene expression, therefore, it plays a critical role in the regulation of the cell cycle, self-renewal capacity, and differentiation of hematopoietic progenitor cells [7]. ETO2 indirectly promoted leukemia stem cells transformation and guided a relapse gene program which induced dismal clinical outcomes in AML [8]. To our knowledge, ve ETO2 fusion genes have been reported in hematological malignancies up to date, including inv(16)(p13.3q24.3)/ETO2-GLIS2 [2,9],t(1;16) (p31;q24)/NFIA-ETO2 [10] and t(16;21)(q22;q24)/RUNX1-ETO2 [11] in AML, t(9;16)(p13;q24)/PAX5-ETO2 [12] in ALL and t(14;16)(q32;q24)/IGH-ETO2 [13] in lymphoma.…”

The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid–induced myeloid gene expression and differentiation in acute myeloid leukemia

“…Underscoring its important role in hematopoietic transcriptional regulation, CBFA2T3 is frequently involved in leukemogenic translocations producing CBFA2T3 fusion proteins, including RUNX1-CBFA2T3 in therapyrelated AML (14) and CBFA2T3-GLIS2 in pediatric AMLs (15). WT CBFA2T3 plays important roles in both normal and malignant hematopoiesis, where it inhibits terminal erythromegakaryocytic differentiation (16), maintains stemness of long-term hematopoietic stem cells (HSCs) (17), and promotes the expansion of leukemia stem cells (LSCs) and AML relapse (18). Intriguingly, CBFA2T3 knockout in murine HSPCs promotes differentiation along the granulo-monocytic lineage at the expense of erythro-megakaryocytic development, phenocopying the effect of ATRA treatment (19,20).…”