Mouse models of caspase-2 deficient nucleophosmin-mutated AML

SUMMARY
Prognosis for relapsed acute myeloid leukemia (AML) is dismal (50% relapse rate, 5-year overall survival less
than 28%), underscoring the critical need for more effective, less toxic therapies. The most frequently mutated
gene in AML is nucleophosmin (NPM1). Mutations in NPM1 (NPM1c+) are leukemia-generating events and often
confer a more favorable prognosis (40% survival). Thus, NPM1c+ AML is defined as a distinct leukemia entity.
However, the advantage associated with NPM1c+ is lost in older patients, in patients with co-occurring mutations,
and in relapsed patients undergoing salvage therapy. Hence, the prognosis of this common type of AML is still
very poor compared to other cancers. Therefore, more interventions that target NPM1c+ AML are critically
needed. This goal is hindered because the mechanisms underlying NPM1c+-induced leukemogenesis and
leukemia maintenance are unclear. In this proposal, the applicant will develop in vivo murine models to
investigate the role of caspase-2 as an essential gene in NPM1c+ AML. This premise is based on preliminary
and published data from the applicant's laboratory that NPM1c+ activates caspase-2, and that caspase-2 loss
leads to cell cycle arrest, terminal differentiation, and downregulation of signaling pathways that regulate stem
cell pluripotency of NPM1c+—but not NPM1wt— AML cells. The central hypothesis of this application is that
NPM1-c+-induced caspase-2 activation promotes AML self-renewal to drive and propagate leukemia. The
specific aims are to: 1) Determine the impact of loss of caspase-2 on self-renewal of NPM1c+ myeloid cells, and
2) Determine how loss of caspase-2 impacts NPM1c+-associated myeloproliferative disease (MPD) and AML.
Under the first aim, established mouse models for inducible NPM1c+ will be crossed to caspase-2-deficient mice
to evaluate the role of caspase-2 in the pre-leukemic state and stem cell expression. Under the second aim, an
inducible Npm1c+ mouse co-expressing a Dnmt3a mutation will be crossed to caspase-2 knockout mice to
determine the effect of caspase-2 loss on MPD and AML development and changes to chromatin accessibility
associated with NPM1c+/Dnmt3a mutant expression. These experiments will provide the essential murine
models and preliminary data to fully investigate caspase-2 as a critical downstream effector of NPM1c+ in AML.
This work will allow the applicant to pursue her long-term goal to advance opportunities for AML treatment, and
provide critical insight into a novel role for caspase-2 as a key regulator of cancer cell pluripotency.

Grant Number: 1R03CA303759-01
NIH Institute/Center: NIH
Principal Investigator: Lisa Bouchier-Hayes