CMLRP 2012 Investigator Vignette

Title: The Role of a Novel Oncogene SALL4 in CML Progression

Investigator: Li Chai, MD; Brigham and Women's Hospital

The object of my grant was focus on study of a novel oncogene. There happened also to be a stem cell factor in CML progression. Chronic myeloid leukemia, CML is a disease that has two phases. Most people presented with a chronic phase, where it is producing a massive amount of so-called normal cells or normal-looking cells. When the disease progresses from the chronic phase to the so-called acute leukemia phase, the whole bone marrow is being turned into making these nonfunctioning cancer cells. They don't take a normal cell appearance as they did before. Now they become so-called blastic cells, and the patient-the reason they die from this is their bone marrow fails to release nonfunctioning cancer cells.

So in the chronic phase, the current treatment is using "Gleevec," which is a BCR-ABL inhibitor to slow down the cells being produced. So that when the patients are on these BCR-ABL inhibitors, they can be in remission for awhile. However they can never be completely cured just because the BCR-ABL inhibitors unfortunately don't touch the so-called cancer stem cells.

What happens is, when during the blood formation there is a range of cell types; all peripheral mitrocells come from a cell type called stems cells, or the mother cells of all type of cells. So apparently, cancer cells also have this preserved structure, which means there is a cancer stem cell that gives rise to a range of different types of cancer cells. So with BCR-ABL inhibitor really not targeting the stem cells or leukemia stem cells.

So the patient may maintain certain remission for years; however, eventually all these patients develop new mutations which do not respond to this treatment and they go on to becoming acute phase, blastic phase. So looking for new target, particular targeting so called leukemia stem cells, I proposed looking at embryonic stem cell factor SALL4, and also an oncogene to see how it works in CML transformation.

And as you can see, this is a chronic CML patient you don't see SALL4 expression at all. The cells keep the normal features. But you can see compared to a female patient already transformed to AML, you have these round very immature looking cells. Those are the acute myeloid leukemia phase and that's how strong this gene is being reactivated. In the chronic phase, this gene is not being expressed. However if you have a leukemia phase, SALL4 being reactivated and SALL4 can work with the BCR-ABL genes and further promote this transformation.

So we know exactly what subpopulation of the leukemia stem cells that the SALL4 are located and then also by looking at this population we're able to find out how SALL4 works. It can recruit protein complex and repress a very key gene called PTEN in this process. And so by those two findings, right now what we're heading to is a concept that you connect cancer-cancer stem cells and also normal developmental differentiation. By tracing down how cell SALL4 works, we actually did indeed find a novel pathway that mediated the transformation from the chronic phase to the acute phase which we are hoping that the next step by looking for drug targets about this pathway we can slow down or stop this transformation process.