Our study supports a critical role for Scd1 in CML development through specifically regulating LSCs but not normal HSCs. In our previously published study, we identified another lipid-metabolic gene, arachidonate 5-lipoxygenase (Alox5
), required for functional regulation of LSCs but not normal HSCs (1
). Our identification of Scd1 in the present study strengthens the feasibility of specifically targeting LSCs in the treatment of CML.
Although dysregulated expression of Scd1 has been observed in several human cancers (32
), to our knowledge the present study provides the first evidence for the role of Scd1 in hematopoiesis and leukemogenesis. Previous data indicated that Scd1
regulated cancer cell proliferation and survival. Knockdown of Scd1
by small interfering RNA significantly reduced the survival of multiple human tumor cell lines (21
). In contrast, in the present study, we found that Scd1 plays a tumor-suppressive role in LSCs through regulating apoptosis of LSCs. This indicates that Scd1 plays different roles in different cancers. In addition, while CML development was accelerated in the loss of Scd1
, the development of Ph+
B-ALL could be unimpaired. It is known that CML is a stem cell disease, while the cell of origin for ALL is a committed B-cell progenitor (16
). Therefore, the distinct roles of Scd1 in different leukemia subtypes suggest that Scd1 acts in a cell-type-specific manner.
With respect to the molecular basis for the functional regulation of LSCs by Scd1, we show that Scd1
deficiency results in dysregulated expression of apoptosis-related genes, including decreased expression of Pten
and increased expression of Bcl-2
, which is consistent with the observation from other groups showing that Scd1
deficiency reduces cardiac apoptosis in ob/ob
mice due to the increased expression of antiapoptotic factor Bcl-2
). In addition, we also show that treatment with PPARγ agonist induces the apoptosis of leukemia cells, which is associated with a higher expression of Scd1
, and p53
. A recent study showed that unsaturated fatty acid affected Pten expression in hepatoma cells through regulating microRNA-mediated Pten mRNA stability, which depends on the mTOR and NF-κB pathways (30
). Our results show that Scd1 regulates Pten, p53, and Bcl2 at the transcriptional and/or posttranscriptional level. However, detailed mechanisms by which Scd1 regulates expression of Pten, p53, and Bcl2 need to be further investigated in the future.
The mechanisms by which a PPARγ agonist inhibits LSCs is unclear. PPARs are ligand-binding transcription factors belonging to the nuclear receptor family. PPARs are involved in regulating lipid metabolism, cell growth, and survival. It has been shown that activation of the PPAR pathway with the dual PPARα and PPARγ ligand TZD18 induces apoptosis and inhibits the proliferation of human CML cells (18
). Although rosiglitazone synergized with imatinib to delay CML development, rosiglitazone alone failed to do so. One possibility is that rosiglitazone alone is not effective enough to prevent lung hemorrhage, a major cause of death of CML mice. Another possibility is that the level of Scd1 induced by rosiglitazone is not high enough to delay CML development. PPAR agonists are anti-inflammatory agents since they inhibit the expression of several proinflammatory cytokines and most chemokines (3
). A role of an anti-inflammatory agent on LSCs is supported by our previous study showing that the anti-inflammatory drug Zileuton, which inhibits the function of the Alox5 gene, prolongs the survival of CML mice (1
). We treated LSCs from CML mice in vitro
with rosiglitazone alone or both rosiglitazone and Zileuton and found that the dual drug treatment resulted in a significantly lower percentage of LSCs compared to treatment with rosiglitazone alone (data not shown), indicating that an Alox5 inhibitor synergizes with PPAR agonist to inhibit LSCs. Together, enhancement of Scd1 activity provides an attractive strategy for eliminating LSCs in CML.