BC scientists have discovered why most patients with myelodysplastic syndrome (MDS) become resistant to the current standard-of-care treatment, answering a long-standing question about this disease.
MDS is a type of blood and bone marrow cancer that often precedes leukemia. There are several subtypes of the disease, but the most common structural genomic variant is the deletion of the long arm of chromosome 5, also known as del(5q) MDS. Patients with this subtype are treated with a drug called lenalidomide. But while this drug is effective at first, most patients eventually become resistant to treatment, meaning their cancer grows.
In a paper published in Nature Cell Biology (May 2020), the team led by Drs. Aly Karsan and Sergio Martinez-Høyer, revealed that mutations in two genes – TP53 and RUNX1 – are responsible for driving resistance to lenalidomide in patients with del(5q) MDS.
The key to making this discovery was to first uncover exactly how lenalidomide works. According to the team, the drug kills cancer cells by forcing them to become more mature – a process known as differentiation. For this to happen, TP53 and RUNX1, two genes responsible for cell differentiation, must be functioning properly. If they are mutated, which tends to occur in these patients, the cancer cells can’t mature and don’t die off, meaning they are able to grow and develop into leukemia cells.
“This is a unique finding because it not only reveals how lenalidomide actually works; it also explains the molecular mechanisms that drive therapy resistance in MDS,” explained Dr. Karsan.
That’s not all. The team also found that TP53 and RUNX1 worked alongside a third gene, called GATA2, to drive differentiation. This made them wonder what would happen if they forced the expression of GATA2 in the lab. What they found was surprising: forcing the expression of the gene helped bypass the mutations in TP53 and RUNX1, thus restoring the differentiation process. In other words, this made cancer cells susceptible to lenalidomide once again.
“While no drugs currently exist to force the expression of GATA2, this finding provides a potential avenue for researchers seeking to develop combination therapies for MDS patients,” said Dr. Karsan.
Loss of lenalidomide-induced megakaryocytic differentiation leads to therapy resistance in del(5q) myelodysplastic syndrome
Sergio Martinez-Høyer, Yu Deng, Jeremy Parker, Jihong Jiang, Angela Mo, T. Roderick Docking, Nadia Gharaee, Jenny Li, Patricia Umlandt, Megan Fuller, Martin Jädersten, Austin Kulasekararaj, Luca Malcovati, Alan F. List, Eva Hellström-Lindberg, Uwe Platzbecker and Aly Karsan
This study was partially funded by a Terry Fox New Frontiers Program Project Grant in Exploiting Pathogenic Mechanisms in Acute Leukemia for Clinical Translation