Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a type of cancer that starts in the blood-forming cells of the bone marrow and invades the blood. About 15% of leukemias in adults are CML. Tyrosine kinase inhibitors (TKI) have helped transformed the prognosis of the disease with fewer side effects compared to other cancer treatments. However, TKIs only control the disease leaving the possibility of drug resistance developing. Thankfully, researchers from Hiroshima University report they have identified a new path to defeating CML. Using mouse models, the researchers found a way to decrease the CML cell growth cycle.

Their findings, “The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukemia stem cells,” were published in Nature Communications and led by Kazuhito Naka, PhD, associate professor from the department of stem cell biology of Hiroshima University’s Research Institute for Radiation Biology and Medicine.

Researchers have made great strides in understanding how certain changes in DNA can cause normal bone marrow cells to become leukemia cells. In no cancer is this better understood than in CML. Each human cell contains 23 pairs of chromosomes. Most cases of CML start during cell division, when DNA is “swapped” between chromosomes 9 and 22. Part of chromosome 9 goes to 22 and part of 22 goes to 9. This is known as translocation and it makes a chromosome 22 that’s shorter than normal.

The swapping of DNA between the chromosomes leads to the formation of a new oncogene called BCR-ABL. This gene then produces the BCR-ABL protein, which causes CML cells to grow and divide out of control.

BCR-ABL1 turns a regular stem cell in the bone marrow into a CML stem cell that produces malformed blood cells. However, instead of the CML stem cell dying when it should be scheduled to do so, the oncogene causes it to keep producing even more of malformed blood cells.

“If CML stem cells are in a quiescent [idling] phase, they are otherwise left untouched by TKI treatment, and so survive to potentially cause a relapse,” explained Naka.

CML stem cells, which are the cellular source of the vast majority of CML cells, are reportedly resistant to TKI therapy due to the stem cell quiescence. Thus, the remaining CML stem cells are responsible for the recurrence after TKI therapy. [Kazuhito Naka, Hiroshima University]
“To identify lipid metabolism-related genes that are differentially expressed in CML stem cells compared to normal WT HSCs [wild-type hematopoietic stem cells], we surveyed an RNA-Seq gene expression profiling dataset that we previously made available to a public database gene expression omnibus,” noted the researchers. “We found that the Gdpd3 gene encoding a lysophospholipase D enzyme was more highly expressed in the most primitive LT-CML stem cells than in normal WT LT-HSCs. This finding prompted us to investigate the biological significance of Gdpd3 and lysophospholipid metabolism in CML stem cells.”

The researchers discovered that if they disrupted Gdpd3, a different non-oncogene gene, then the self-renewal capacity of the CML stem cells decreases significantly.

“Although signaling pathways related to lipid mediators are known to be involved in regulating CML stem survival, prior to our work, there had been little understood about how lipid biogenesis contributes to the self-renewal capacity of CML stem cells,” explained the researchers. “In this study, we have shown that CML-LSK cells lacking the lysophospholipase D Gdpd3 display decreased self-renewal capacity in the second-round of serial [bone marrow transplantation] BMT. More importantly, Gdpd3/ CML-LSK cells show attenuated disease-relapsing capacity in animals treated with dasatinib.”

Gdpd3 hydrolyzes lysophospholipids into LPAs. Gdpd3 deficiency activates the cell proliferative capacity in CML stem cells, and improves the recurrence of CML-affected mice after treatment with TKI dasatinib. [Kazuhito Naka, Hiroshima University]
“This potentially provides another path to arresting these leukemias—and maybe other cancers too,” said Naka, “beyond having to wrestle with the BCR-ABL1 oncogene.”

Although the researchers identified a new role for Gdpd3 in causing the recurrence of CML, they are looking to investigate the mechanisms involved and whether this lipid also plays a role in the idling of the cancer stem cells that cause solid tumors, not just in leukemias, and thus in these cancers’ recurrence and growth as well.

Their findings provide hope and may one day lead to new therapies in the prevention of AML relapse, especially in the face of drug resistance.

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