CONTRADICTING EVIDENCE: In this report, we describe a patient with NRAS-G12D-positive aCML who experienced an exceptional response to MEK1/2 inhibition with trametinib. The patient demonstrated rapid improvements in his blood counts and reported symptomatic improvement with an increase in energy level within several months after starting therapy. The response to trametinib has been quite durable with the patient experiencing an ongoing near-complete hematologic response after 14 months of therapy.

As in vitro models of JMML, we generated inducible pluripotent stem cells (iPSC) stably expressing wildtype or activating oncogenic versions of KRAS (G12D) or NRAS (G13D) as well as iPSCs with CRISPR interference mediated downregulated NF1 expression…In our screen the model cell lines were resistant to all tested MEK-inhibitors, including Selumetinib and Trametinib. The broad receptor tyrosine kinase inhibitor Dovitinib and the DNA methyltransferase inhibitor Azacytidine elicited strong responses in all iPSC cell lines regardless of their KRAS, NRAS or NF1 state.