Nature: The key to the transformation of chronic blood cancers into aggressive diseases

A chronic type of leukemia can remain latent for years
.
Some patients may need treatment to control this type of blood cancer, a myeloproliferative tumor (MPN), while others may need to wait for a long time to watch
.
But for a small percentage of patients, this slow disease can transform into an aggressive cancer called secondary acute myeloid leukemia, which has few effective treatment options
.
Little is known about how this shift took place
.

But now, researchers at Washington University School of Medicine in St.
Louis have identified an important turning point
in the transition from chronic leukemia to aggressive leukemia.
They have shown that blocking a key molecule in the transition pathway prevents this dangerous disease progression
in mice with models of the disease and mice with tumor samples taken from human patients.

The study was published Dec.
29 in the journal Nature Cancer
.

"The prognosis for secondary acute myeloid leukemia is poor," said
senior author Dr.
Stephen T.
Oh, associate professor of medicine and co-director of the Division of Hematology in the School of Medicine.
"Almost every patient with acute leukemia with a history of myeloproliferative tumors dies from this disease
.
Therefore, the main focus of our research is to better understand this transition from chronic to aggressive disease and to develop better treatments for these patients, and hopefully provide prevention strategies
for these patients.
”

This study suggests that inhibiting this key transition molecule, known as DUSP6, helps overcome the resistance these cancers normally develop to JAK2 inhibitors, commonly used in therapies to treat them
.
JAK2 inhibitors are an anti-inflammatory therapy that is also used to treat rheumatoid arthritis
.

"These patients are typically treated with JAK2 inhibitors, but despite this treatment, their disease is progressing, so we're also trying to determine how the disease worsens even in the case of JAK2 suppression," said
Oh, who is treating patients at the Siteman Cancer Center at Barnes-Jewish Hospital and the University of Washington School of Medicine.

The researchers delved into the genetics of these tumors, including during a slow chronic phase and after
the disease transitioned to an aggressive form when patients took JAK2 inhibitors.
In the 40 tumor patients analyzed in this study, the DUSP6 gene was highly expressed
.

Deleting the DUSP6 gene using genetic techniques could prevent the transition
to aggressive disease in mice in this cancer model.
The researchers also tested a drug compound that inhibits DUSP6 and found that this compound (used only in animal studies) prevented the progression
of chronic disease to aggressive disease in two different mouse models of cancer and in mice with human tumors sampled from patients.
In these models, lowering DUSP6 levels through genes and drugs also reduced inflammation
.

Since drugs that inhibit DUSP6 cannot be used in human clinical trials, Oh and his colleagues are interested in exploring treatments that inhibit the downstream activation of DUSP6 with another molecule that they found is also necessary to
perpetuate the negative effects of DUSP6.
In clinical trials, there are drugs that inhibit this downstream molecule, known as RSK1
.
Oh's team is interested in studying these drugs because of their potential to stop the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition
.

"Future clinical trials may recruit patients with myeloproliferative tumors who are taking JAK2 inhibitors, but nevertheless, there is evidence of worsening of their disease
," Oh said.

"At that point, we may add the types of RSK inhibitors currently in trials to their treatment to see if that helps stop the disease from progressing to aggressive secondary acute myeloid leukemia
.
" A newly developed RKS inhibitor is undergoing Phase I clinical trials in breast cancer patients, so we hope that our work provides a promising basis
for developing new therapeutic strategies for patients with this chronic blood cancer.
" ”