Synergistic effects of ASXL1 and BCOR on hematopoiesis and MDS/AML progression Free

Background: Myelodysplastic syndromes (MDS) and MDS-transformed acute myeloid leukemia (AML) are hematologic malignancies that pose a serious threat to human health. Hematopoietic stem cell transplantation (HSCT) is currently a key treatment to extend survival and reduce relapse in these patients. However, the molecular mechanisms driving disease progression, especially the role of specific mutations, remain poorly understood. Clinical evidence suggests that co-occurring mutations, such as those in ASXL1 and BCOR, may interact to accelerate disease progression.

Methods: We investigated the impact of ASXL1 and BCOR mutations on hematopoietic development and disease progression using clinical case observations and zebrafish models. A high-risk MDS-transformed AML patient with ASXL1(p.G652S) and BCOR (p.E1694GfsTer31) mutations was analyzed before and after receiving HSCT from an ASXL1-mutant sibling donor. Zebrafish models with single and double mutations in asxl1 and bcor were generated to examine the effects of these mutations on hematopoietic development and progression to MDS/AML.

Results: In our clinical center, we encountered a case of high-risk MDS transformed to AML. The patient, initially carrying ASXL1 (p.G652S) and BCOR (p.E1694GfsTer31) mutations, achieved complete remission after receiving HSCT from an elder sister who also carried the ASXL1 (p.G652S) mutation. At this point, bone marrow cells retained the ASXL1 (p.G652S) mutation but showed no trace of the BCOR mutation. However, on day 131 post-transplantation, the patient experienced a relapse of MDS. Next-generation sequencing (NGS) of bone marrow cells revealed the reappearance of the ASXL1 (p.G652S) mutation along with a newly identified BCOR truncating mutation (p.R1547*; c.4428+1G>A). After being treated with decitabine maintenance therapy, the patient achieved MDS remission, and no BCOR mutations were detected on day 286 post-transplantation. Based on these findings, we hypothesize that BCOR mutations may play a critical role in accelerating MDS/AML progression.

To explore this further, we utilized the zebrafish model and constructed asxl1 mutants, bcor mutants, and asxl1/bcor double mutants. Our previous research revealed that asxl1 mutants displayed abnormal early hematopoietic development, with significantly reduced early myeloid cells marked by lyz. On the other hand, bcor mutants exhibited a reduction in early lymphoid cells marked by rag1 and a slight decrease in early myeloid cells marked by lyz. Interestingly, in asxl1/bcor double mutants, myeloid cells marked by lyz were robustly reduced compared to either single mutant. These results suggest that bcor deficiency exacerbates the phenotype of myeloid cell reduction and that asxl1/bcor double mutations might profoundly impact the development and function of normal blood cells starting from early embryonic stages. Additionally, our prior studies showed that asxl1 mutants spontaneously develop MDS or AML phenotypes within 1 to 1.5 years. In contrast, no MDS phenotypes were observed in bcor single mutants during the same timeframe. Strikingly, in asxl1/bcor double mutant zebrafish, we detected a significant increase in abnormal myeloid precursor cells as early as 9 months, indicative of MDS/AML phenotypes.

Conclusions: Based on these data, we hypothesize that the occurrence of BCOR mutations in the presence of ASXL1 mutations acts as a disease accelerator, impairing the normal development of hematopoietic cells and thereby promoting the onset and progression of MDS/AML.