Image by Tom Ellenberger
PARP inhibitors could prove useful for treating aggressive acute myeloid leukemia (AML), according to preclinical research published in Nature Medicine.
Experiments showed that AML driven by leukemia-associated transcription factors, including AML1-ETO and PML-RARα, was “extremely sensitive” to PARP inhibition.
Mixed-lineage leukemia (MLL) was initially resistant to treatment with PARP inhibitors, but inhibiting Hoxa9 changed that.
“PARP inhibitors could potentially offer a completely different approach to specifically target certain subtypes of acute myeloid leukemia,” said study author Chi Wai Eric So, PhD, of King’s College London in the UK.
He and his colleagues first tested the PARP inhibitor olaparib on primary mouse hematopoietic cells transformed by the leukemia-associated transcription factors AML1-ETO, PML-RARα, MLL-AF9, and E2A-PBX.
The drug suppressed the colony-forming ability of cells transformed by AML1-ETO or PML-RARα by about 90% but had little impact on MLL-AF9- or E2A-PBX-transformed cells. Olaparib also had minimal effects on normal bone marrow.
The investigators observed similar results in experiments with the PARP inhibitor veliparib.
They then tested PARP inhibitors in patient-derived leukemic cell lines carrying AML1-ETO (Kasumi), mutated PML-RARα that is resistant to standard all-trans retinoic acid treatment (NB4-LR2), or MLL-AF9 (THP1).
Similar to the previous experiments, PARP inhibition reduced the colony-forming ability of Kasumi and NB4-LR2 cells but not THP1 cells.
Next, the investigators transplanted the 3 cell lines into immunocompromised mice and treated the mice with olaparib. The drug delayed disease onset and prolonged survival in both the Kasumi and NB4-LR2 models but had no effect on disease onset or survival in the THP1 model.
Dr So and his colleagues said PARP inhibition was likely effective in AML driven by AML1-ETO and PML-RARα because of the suppressed expression of key homologous recombination-associated genes and the compromised DNA-damage response observed in these malignancies.
The team noted that PARP has proven critical in a variety of DNA repair processes, including as a sensor of single-strand breaks in base-excision repair, as a mediator for restarting stalled replication forks of homologous recombination-mediated double-strand break repair, and as a means of preventing the binding of Ku proteins to DNA ends in non-homologous end-joining pathways.
It therefore follows that MLL-driven AML was resistant to treatment with PARP inhibitors because DNA repair is not suppressed in this malignancy. The Hoxa9 protein activates other DNA damage repair pathways in these leukemia cells, keeping them alive.
So the investigators tested drugs that could (indirectly) inhibit Hoxa9—the GSK3 inhibitors LiCl and Li2CO3—in combination with olaparib. Both in vitro and in vivo, treatment with a GSK3 inhibitor and olaparib proved effective against MLL-driven AML.
“While this approach seems promising from these laboratory studies, it is still very early days,” said Matt Kaiser, PhD, head of research at Bloodwise, a charity that helped fund this study.
“We need to see how real patients respond to these drugs and how effective they are. PARP inhibitors such as olaparib are already being used to treat patients with other cancers and have been shown to be safe. This should speed up the time it takes for this potentially effective new treatment to enter clinical trials.”
