RUNX1–ETO Upregulates CCND2 to Drive Leukemogenesis

A subset of acute myeloid leukemias (AML) are driven by the RUNX1–ETO transcription factor fusion protein, which is generated by a recurrent t(8;21) translocation. RUNX1–ETO is an attractive therapeutic target as it is tumor specific, but has been challenging to inhibit directly, suggesting the potential for targeting other components of the RUNX1–ETO network. To discover putative therapeutic targets, Martinez-Soria, McKenzie, and colleagues performed an RNAi screen to identify RUNX1–ETO target genes. This screen uncovered CCND2 (Cyclin D2) as a target gene upregulated by RUNX1–ETO expression. RUNX1–ETO occupied an upstream element of the transcription start site of CCND2, and cooperates with the transcription factor complex AP1 (comprised of JUN and FOS), which drives transcription and cell-cycle progression. Depleting AP1 or CCND2 inhibited proliferation and induced cell-cycle arrest of RUNX1–ETO-positive leukemia cells. CCND2 binds to CDK4 and CDK6, and RUNX1–ETO-positive leukemia cells were sensitive to treatment with the CDK4/6 inhibitor palbociclib. In vivo, palbociclib reduced disease progression and extended survival in mice with RUNX1–ETO leukemia. Secondary KIT mutations occur frequently in RUNX1–ETO-positive AML, and palbociclib treatment sensitized RUNX1–ETO-positive cells to KIT inhibition, suggesting that dual inhibition of CDK4/6 and KIT may enhance the antitumor activity. In addition to identifying CCND2 as a RUNX1–ETO target gene and essential component of RUNX1–ETO-driven tumorigenesis, these findings suggest that patients with RUNX1–ETO-positive AML may potentially benefit from CDK4/6 inhibition alone or in combination with KIT inhibition. This may represent an effective therapeutic approach to indirectly target RUNX1–ETO in AML.

Martinez-Soria N, McKenzie L, Draper J, Ptasinska A, Issa H, Potluri S, et al. The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation. Cancer Cell 2018;34:626–42.

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