Recurrent SETD2 mutation in NPM1-mutated acute myeloid leukemia

Abstract

SETD2 is the only methyltransferase for H3K36me3, and our previous study has firstly demonstrated that it functioned as one tumor suppressor in hematopoiesis. Consistent with it, SETD2 mutation, which led to its loss of function, was identified in AML. However, the distribution and function of SETD2 mutation in AML remained largely unknown. Herein, we integrated SETD2-mutated AML cases from our center and literature reports, and found that NPM1 mutation was the most common concomitant genetic alteration with SETD2 mutation in AML, with its frequency even higher than MLL rearrangement and AML1-ETO. Though this result indicated the cooperation of SETD2 and NPM1 mutations in leukemogenesis, our functional study showed that SETD2 was required for the proliferation of NPM1-mutated AML cell line OCI-AML3, but not MLL-rearranged AML cell line THP-1, via maintaining its direct target NPM1 expression, which was just opposite to its role of tumor suppressor. Therefore, we speculated that SETD2 possibly had two different faces in distinct subtypes and stages of AML.

New insights into the clinical characteristics of SETD2‐mutated acute myeloid leukaemia

“…By contrast, the knowledge of SETD2 mutation in AML is still poorly understood. Recently, some sporadic studies have shown that SETD2 mutation is recurrent in KMT2A ‐rearranged and CBF ‐rearranged AML 4 . Our results showed SETD2 mutation to occur frequently in NPM1 ‐mutated AML 6 .…”

“…Our previous study showed that Setd2 deficiency in the haematopoietic system led to the malignant transformation, which provided evidence of its tumour suppressor role in haematopoiesis 1,2 . Consistently, SETD2 mutation has been found to affect 12% of acute lymphoblastic leukaemia (ALL) and 8% of acute myeloid leukaemia (AML) 3,4 . In ALL, the distribution pattern of SETD2 mutation has been well established.…”

“…In ALL, the distribution pattern of SETD2 mutation has been well established. Previous findings have indicated that SETD2 mutation tends to co‐occur with KMT2A rearrangements, ETV6::RUNX1 and TCF3::PBX1 3–5 . By contrast, the knowledge of SETD2 mutation in AML is still poorly understood.…”