Image from Armed Forces Institute of Pathology
Micrograph showing AML
The AP-1 transcription factor family is of “major importance” in acute myeloid leukemia (AML), according to researchers.
The team said they identified transcription factor networks specific to AML subtypes, which showed that leukemic growth is dependent upon certain transcription factors, and “the global activation of signaling pathways parallels a growth dependence on AP-1 activity in multiple types of AML.”
Constanze Bonifer, PhD, of the University of Birmingham in the U.K., and her colleagues conducted this research and detailed their findings in Nature Genetics.
The researchers noted that previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA methylation patterns.
“Our work now defines these networks in detail and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” Dr. Bonifer and her colleagues wrote.
The researchers combined data obtained via several analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from AML patients with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.
The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the team reported.
Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.
In the in vitro study, the researchers transduced AML cells with a doxycycline-inducible version of a dominant-negative (dn) FOS protein.
“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB, and JDP families of transcription factors,” the researchers wrote. “[T]hus, it is challenging to target by defined RNA interference approaches.”
Results of the in vitro study showed that induction of dnFOS, mediated by doxycycline, inhibited proliferation of t(8;21)+ Kasumi-1 cells and FLT3-ITD-expressing MV4-11 cells.
Induction of dnFOS also inhibited the colony-forming ability of primary CD34+ FLT3-ITD cells but not CD34+ hematopoietic stem and progenitor cells.
To evaluate the relevance of AP-1 for leukemia propagation in vivo, the researchers transplanted either of two cell lines—Kasumi-1 or MV4-11—expressing inducible dnFOS in immunodeficient mice.
With Kasumi-1, granulosarcomas developed in six of seven untreated control mice and two mice treated with doxycycline, neither of which expressed the inducible protein.
With MV4-11, doxycycline inhibited leukemia development, and untreated mice rapidly developed tumors.
The researchers declared no competing interests related to this work, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship, and an MRC/Leuka Clinical Training Fellowship.