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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.

Under the differentiation induction therapy with all‐trans retinoic acid and arsenic trioxide, nearly 95% of typical acute promyelocyte leukemia (APL), which is characterized by the presence of PML‐RARA, patients can be cured. Though its good prognosis, if left untreated, the natural survival duration of typical APL patients is only 1 month, but some exceptional cases also exist. Occasionally, we have observed the entire natural clinical course of one extremely indolent APL patient, who developed from pre‐APL stage (<20% promyelocytes in bone marrow) to overt‐APL stage (≥20% promyelocytes in bone marrow) with one nearly 2‐year latency. Strikingly, we identified one novel fusion RBCK1‐TRIB3 in the pre‐APL stage but not overt‐APL stage sample. It has been reported that TRIB3 stabilized PML‐RARA to driver APL progression, while RBCK1‐TRIB3 partially disrupted TRIB3WT expression, so it contributed to the deceleration of APL progression in this patient.