Abstract
The E3 ubiquitin ligase and tumor suppressor APC/CCdh1 is crucial for cell cycle progression, development and differentiation in many cell types. However, little is known about the role of Cdh1 in hematopoiesis. Here we analyzed Cdh1 expression and function in malignant hematopoiesis. We found a significant decrease of Cdh1 in primary acute myeloid leukemia (AML) blasts compared to normal CD34+ cells. Thus, according to its important role in connecting cell cycle exit and differentiation, decreased expression of Cdh1 may be a mechanism contributing to the differentiation block in leukemogenesis. Indeed, knockdown (kd) of Cdh1 in HL-60 cell line (AML with maturation, FAB M2) led to less differentiated cells and a delay in PMA-induced differentiation. Acute promyelocytic leukemia (APL, FAB M3) is an AML subtype which is highly vulnerable to differentiation therapy with all-trans retinoic acid (ATRA). Accordingly, we found that APL is resistant to a Cdh1-kd mediated differentiation block. However, further depletion of Cdh1 in APL significantly reduced viability of leukemia cells upon ATRA-induced differentiation. Thus, low Cdh1 expression may be important in AML biology by contributing to the differentiation block and response to therapy depending on differences in the microenvironment and the additional genetic background.
Highlights
In the hematopoietic system balance between cell cycle progression on the one hand, and cell differentiation preceded by cell cycle exit on the other hand, is vital
We analyzed the Cdh1 expression of acute myeloid leukemia (AML) cell lines NB4 and HL-60 and found that Cdh1 in both AML cell lines was much lower expressed and about half of what we observed in peripheral blood (PB) CD34+ control samples (Figure 1D, 1E).we confirmed that the cell lines were comparable to primary samples
While we found Cdh1 expression decreased in the vast majority of primary AMLs of all subtypes, Cdh1 deficiency contributes to the differentiation block in AML with maturation but not in acute promyelocytic leukemia (APL)
Summary
In the hematopoietic system balance between cell cycle progression on the one hand, and cell differentiation preceded by cell cycle exit on the other hand, is vital. Its coactivator Cdh is needed to establish a stable G0/G1 phase, which is an important precondition for precise cell cycle progression or differentiation and maintenance of genomic stability [3,4,5,6,7,8]. Loss of Cdh may contribute to tumorigenesis by enhanced proliferation of undifferentiated and genetically unstable cells [9] It has been shown in various models that APC/ CCdh establishes a stable G1/G0 phase by maintaining a low mitotic cyclin state [10,11,12,13] and degrading the F box protein Skp, which leads to the stabilization of the SCFSkp targets and Cdk inhibitors p21 and p27 [14, 15]. Other important APC/CCdh targets to control the differentiation process are Id (inhibitor of differentiation) proteins [8]
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