3 - Discussion:
Identification of targetable lesions in AML provides clinicians with
novel treatment options to improve clinical outcomes for patients who
respond poorly to current conventional chemotherapy, such as patients
with Monosomy 7 AML. With ongoing discovery efforts and further
interrogation of large patient repositories, we hope to identify
additional novel targets, particularly for patients with rare subtypes
of AML.
Here, we demonstrate that newly discovered ALKfus in
Mono7 AML leads to a functional ALK protein with the ability to
transform cells and induce a proliferative advantage in a
cytokine-independent manner. We show cells harboring the
ALKfus to be susceptible to the ALK inhibitor
crizotinib, inducing tumor cell death in the context of AML in
vitro modeling systems. We hypothesize treatment with newer generations
of ALK-inhibitors will result in more robust tumor cell killing and
warrants additional evaluation for exploration. Additionally, to
evaluate the preclinical efficacy of treating ALKfusAML with ALK-inhibitors, such as crizotinib, future in vivoexperiments should be performed. The data presented here provide
rationale for ongoing exploration of crizotinib as an effective
therapeutic option for these high-risk patients with Monosomy7 AML.