The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia

PROJECT SUMMARY (ABSTRACT):
Title: The role and therapeutic potential of IGF2BP2 in MLL-rearranged leukemia.
Background: N6-methyladenosine (m6A) modification is the most abundant internal modification in
eukaryotic messenger RNAs (mRNAs) and plays roles in many normal bioprocesses. Evidence is emerging that
the aberration in m6A modification and the associated machinery also plays important roles in various types of
cancers. Acute myeloid leukemia (AML) is one of the most common forms of hematopoietic malignancies with various
cytogenetic and molecular abnormalities. The mixed-lineage leukemia (MLL)-rearranged (MLLr) AML is a common
and fatal subtype of AML, which accounts for 5%-10% of “de novo” AML cases and 10%-15% of therapy-related
leukemia (t-AML) cases. MLLr AML patients are associated with poor outcomes, with a 5-year overall survival
(OS) rate of ~30%. Therefore, there is a critical unmet medical need to develop improved therapeutics for
MLLr AML treatment. The leukemia stem/initiating cells (LSCs/LICs) are considered to be the root cause for the
treatment failure and relapse of AML. Collectively, it is critical to better understand the molecular mechanisms underlying
MLLr AML pathogenesis and LSC/LIC self-renewal, which may lead to the development of improved novel therapeutic
strategies to treat MLLr AML. Our preliminary data showed that IGF2BP2, which encodes an m6A reader, is specially
overexpressed in MLLr AML and its increased expression is associated with a poor prognosis in AML patients.
Our preliminary functional studies suggest that IGF2BP2 likely plays a critical oncogenic role as an m6A reader
in promoting MLLr AML pathogenesis. IGF2BP2 is also expressed at a significantly higher level in MLLr
LSCs/LICs compared to healthy hematopoietic stem/progenitor cells (HSPCs) and bulk MLLr AML cells, implying
a role of IGF2BP2 in MLLr LSC/LIC self-renewal. In addition, we have developed a potent inhibitor (namely
CWI1-2) that targets IGF2BP2 directly and exhibits high anti-leukemia efficacy as shown in our preliminary
studies.
Hypothesis: IGF2BP2 plays an essential role in MLLr AML pathogenesis and LSC/LIC self-renewal, and
that pharmacological inhibition of IGF2BP2 can lead to effective treatment of MLLr AML.
Specific Aims: 1) Determine the role of IGF2BP2 in MLLr AML pathogenesis and LSC/LIC self-renewal; 2)
Decipher the molecular mechanism underlying the role of IGF2BP2 in MLLr AML; and 3) Assess the therapeutic
potential of pharmacologically targeting IGF2BP2 in treating MLLr AML.
Potential Impact: Our proposed studies are of high novelty and high significance in both basic research and
translational medicine, which will substantially advance our understanding of the biology of MLLr leukemia, and
may also result in the development of effective novel therapeutics for the treatment of MLLr leukemia.

Grant Number: 5R01CA271497-04
NIH Institute/Center: NIH
Principal Investigator: Jianjun Chen