mRNA stability and its impact on hematopoiesis and acute leukemia

Abstract
This application focuses on acute myeloid leukemia (AML), a blood cancer that is characterized by low
survival rates and few available targeted therapies. The five-year overall survival rate for AML is below
30 percent in adults and around 65% in children. Interestingly, one type of intervention that has been
successful for a subtype of AML (acute promyelocytic leukemia, APL) is a “differentiation” therapy,
where drugs can induce tumor cell differentiation and apoptosis. Here we present surface antigen-
guided, CRISPR/CAS9 differentiation screens in AML and study one of the most prominent hits in these
screens, the RNA binding protein (RBP) ZFP36L2. RBPs can modify RNA at multiple levels, including
splicing, processing, modification and degradation. Considering that RBPs are key regulators of gene
expression, alterations of these proteins are also implicated in several human genetic diseases,
including cancer. Our laboratory has recently presented CRISPR/CAS9 screening of RBPs in several
types of human leukemia and identified novel regulators of the spliceosome machinery in blood cancers.
Our CRISPR screens identified ZFP36L2, a member of the TIS11/TTP zinc-finger containing family of
RBPs, that also includes the ZFP36 and ZFP36L1 paralogs. We were able to show that ZFP36L2 binds
AU-rich elements on 3’ untranslated regions (UTRs) of a number of mRNAs that that control early
hematopoietic and myeloid differentiation. This interaction promotes target mRNA degradation and the
maintenance of an undifferentiated state. These studies showed that ZFP36L2 can bind and degrade
the two other members of the TIS11/TTP family, ZFP36 and ZFP36L1, creating a potential additional
level of post-transcriptional regulation of differentiation. Inhibition of ZFP36L2 restores mRNA stability
of targeted transcripts and triggers leukemia cells to undergo myeloid differentiation and eventual
apoptosis. Epigenomic profiling of a number of primary AML patients revealed enhancer modules
nearby ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic
and post-transcriptional mechanism that shapes leukemic differentiation. In this application we initially
(Aim 1) focus on the in vivo role of ZFP36L2 in AML and identify mRNAs, direct targets that can control
AML cell differentiation and growth. In Aim 2, we study all three members of the ZFP36/TIS11 family
and study in detail their roles in hematopoiesis and myeloid leukemia.

Grant Number: 5R01CA266212-04
NIH Institute/Center: NIH
Principal Investigator: Iannis Aifantis