Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice

Keywords: AEL, BCOR, DNMT3a, GATA1

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The BCL6 co-repressor (BCOR) is a member of the non-canonical multimeric polycomb group repressive complex 1 (PRC1), a molecular machinery involved in the control of various biological processes, including pluripotency, reprogramming, and hematopoiesis (1-4). In 2011, we identified recurrent loss-of-function mutations of BCOR  gene in AML and found that they frequently co-occurred with DNA methyl-transferases 3A (DNMT3A) mutations (40% of cases) (5). Interestingly, these mutations were mutually exclusive with FLT3-ITD and NPM1 mutations, and were associated with poor outcomes. Recent acquisitions from next-generation sequencing identified the cooperativity between DNMT3A and BCOR mutations in patients affected by acute erythroid leukemia (AEL) (6), an aggressive myeloid neoplasm with an expected median survival of only 3 months in adults.

Since BCOR and DNMT3A are known epigenetic modifiers, each one known to be implicated in myeloid malignancies, we hypothesized that their combined disruption may promote AML in vivo. In this study, we investigate the effects of BCOR and DNMT3A losses to drive AEL in vivo by means of a newly generated mouse model knocking-out BCOR and DNMT3A (DNMT3A-BCOR KO) genes in hematopoietic system; in addition, we validate DNMT3A-BCOR KO mouse model as a platform for preclinical drug testing in AEL.

To achieve this, at first, we generated BCOR conditional knock-out (cKO) mice, resulting in BCOR loss in hematopoietic system and then we crossed BCOR KO with DNMT3A KO mice, to finally compose the BCOR-DNMT3A double KO mice cohort.  Mice lacking Bcor showed an expansion of myeloid and megakaryocytic-erythroid progenitors, resulting in macrocytic anemia and thrombocytosis, while no features of overt acute leukemia were observed; thus, this finding confirms that BCOR deficiency is not itself sufficient to promote acute leukemia in mice, thus suggesting that other cooperative events are required for AML development in vivo. On the other hand, double KO BCOR-DNMT3A mice rapidly developed a lethal leukemic phenotype, characterized by the expansion of an erythroid lineage precursors/immature erythroid cells, that was consistent with pathological and immunophenotipic diagnosis of AEL.

Gene-expression profiling (GEP) of hematopoietic stem and progenitor cells revealed that this aberrant erythroid skewing was induced by an altered erythroid-specific transcriptional factors program (GATA1-2) that remarkably affect major cell-cycle regulators (Mdm2 and TP53). By interpolating our GEP data with those reported in human AEL samples (6), we identified a molecular signature that included several interactors of GATA1; we then tested the efficacy of Decitabine (an hypomethylating agent) compared to Cytarabine (standard chemotherapy) in our AEL mice cohort, and then proved a significant impact of decitabine on leukemic progression and median overall survival.

In this study, we have demonstrated that BCOR loss perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss to drive murine AEL in vivo, thus providing also the first pre-clinical model of compound DNMT3A-BCOR KO AEL. We described novel molecular networks, potentially involved in AEL development, that obviously warrant further investigations. We also showed that decitabine was superior to cytarabine in influencing AEL course and median survival, thus confirming the intrinsic resistance of this aggressive blood neoplasm to standard chemotherapy, as it is commonly observed in human patients. In summary, our model can be a promising tool to dissect biological underpinnings of AEL biogenesis and maintenance, as serves as a drug-testing platform for rapid translation of therapeutics into human AEL.

References

  1. Huynh KD, Fischle W, Verdin E, Bardwell VJ. BCOR, a novel corepressor involved in BCL-6 repression. Genes & Development. 2000;14(14):1810-1823.
  2. Surapornsawasd T, Ogawa T, Moriyama K. Identification of nuclear localization signals within the human BCOR protein. Febs Letters. 2015;589(21):3313-3320.
  3. Isshiki Y, Iwama A. Emerging role of noncanonical polycomb repressive complexes in normal and malignant hematopoiesis. Experimental Hematology. 2018;68:10-14.
  4. Vidal M, Starowicz K. Polycomb complexes PRC1. and their function in hematopoiesis. Experimental Hematology. 2017;48:12-31.
  5. Grossmann V, Tiacci E, Holmes AB, Kohlmann A, Martelli MP, Kern W, et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood. 2011;118(23):6153-6163.
  6. Iacobucci I, Wen J, Meggendorfer M, Choi JK, Shi L, Pounds SB, et al. Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nature Genetics. 2019;51(4):694-704.

Daniele

Sorcini, Università degli Studi di perugia

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