Mutation of KDM6A Gene in Relapsed Acute Myeloid Leukemia

With the exception of bladder cancer, the frequency of KDM6A gene mutations in malignancy is thought to be rather low in malignant developments. A new study published in Leukemia is suggesting that the loss of KDM6A in patients with acute myeloid leukemia (AML) may provide cells with a selective advantage during chemotherapy, leading to the development of clones with KDM6A mutations or reduced KDM6A expression at the time of relapse. A majority of patients with AML relapse due to intrinsic or acquired drug resistance. German researchers analyzed paired diagnosis and relapse samples of 50 cytogenetically normal (CN) AML patients and discovered that KDM6A appears to be a novel relapse-associated gene in AML.

Sophie M. Stief with the University Hospital, LMU Munich, Munich, Germany, and colleagues found that KDM6A expression is heterogeneously regulated and that relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with cytarabine and daunorubicin, according to the researchers. In a multi-step process, they found that inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells to cytarabine treatment.

The team conducted an RNA expression analysis and additional functional studies and discovered that resistance to cytarabine resulted from the downregulation of the nucleoside membrane transporter ENT1 by reduced H3K27 acetylation at the ENT1 locus. “Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse,” wrote the authors.

The research team used diagnosis, relapse samples from AML patients, patient-derived xenografts (PDX), and leukemia cell lines, to investigate the status of KDM6A during disease progression. They also examined the impact of KDM6A loss on chemotherapy resistance. They found three AML patients with enrichment of KDM6A loss-of-function mutations at relapse and relapse-specific loss of KDM6A mRNA and protein expression. The researchers further compared KDM6A expression in matched diagnosis and relapse samples of 9 AML patients with no detectable KDM6A mutation and concluded that KDM6A inactivation either by mutations or protein downregulation mediates drug resistance in AML

When the researchers compared KDM6A expression in matched diagnosis and relapse samples of 9 AML patients with no detectable KDM6A mutation, they discovered a strong decrease in KDM6A protein expression at relapse in 4 patients while 3 patients showed increased expression at relapse. With further analysis of KDM6A mRNA regulation in 35 CN-AML patients, the team found a downregulation of KDM6A in 45.7% of patients ( 16 of 35) and an upregulation in 37.1% of patients (13 of 35).

Tapan M. Kadia, MD, who is in the Department of Leukemia in the Division of Cancer Medicine at MD Anderson Cancer Center, Houston, Texas, said these findings have the potential to change clinical practice if they are validated in future studies. “Although there may be some relevance for clinical care in the future, it is not immediately impactful at this time. The study could form the basis for additional clinical studies looking at KDM6A mutations in AML patients, their presence at relapse, and their differential sensitivity to cytarabine-based chemotherapy,” Dr. Kadia told Cancer Network.

He said monitoring for these mutations or loss of function of KDM6A in the future could identify subgroups of patients with AML who might be at higher risk for relapse/resistance after cytarabine-based therapy and could be considered for other novel approaches.
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References:

1) Stief SM, Hanneforth A-L, Weser S, et al. Loss of KDM6A confers drug resistance in acute myeloid leukemia. Leukemia. 2019 Jun 14. doi: 10.1038/s41375-019-0497-6. [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/31201358