The POT1 gene is located in chromosome 7 and encodes a key component of the shelterin complex, which is essential for the maintenance of telomere and chromosome integrity. Somatic mutations of POT1 have been identified in chronic lymphocytic leukemia, which indicates that POT1 dysfunction is involved in the pathogenesis of hematological neoplasms. At the same time, abnormal telomere shortening has been observed in MDS/AML and a spectrum of bone marrow failure syndromes. We therefore sought to study the potential role of POT1 in MDS by sequencing the gene and characterizing its expression in primary bone marrow specimens of patients with MDS.

We first sequenced all POT1 coding regions that are known to have mutations in CLL. PCR-Sanger sequencing was performed in bone marrow mononuclear cells (BM-MNNC) of a cohort of 30 patients with MDS (15 with RAEB/RAEBT, 11 with RA/RARS/RCMD/MDS-U, 2 with CMML, and 2 with 5q- syndromes). No genetic mutations in the POT1 gene were detected. This result suggests that genetic alteration of POT1 is rare in MDS.

We then evaluated the expression of POT1 using cDNA arrays (n=183) or RT-PCR (n=58) in a cohort of 241 patients with MDS from two centers. The median age of our patients was 71 years (32-95). Diagnoses included RAEB in 108 (45%), 5q- syndrome in 18 (8%), and other syndromes (RA, RCMD, and MDS-U) in 115 (47%) cases. In this cohort, 140 (58%) patients were diploid, 22 (9%) had chromosome 7 alterations, 21 (9%) had 5q deletion, and 58 (24%) had other cytogenetic abnormalities.

Results indicate that POT1 was underexpressed (less than 50% of the POT1 level in normal controls) in the bone marrow CD34+ hematopoietic progenitor cell population in 138 patients (57%). However, no significant difference was observed between the whole MDS cohort and control BM CD34+ cells from healthy donors (n=25). Further subset analysis based on karyotypes revealed that 81% of patients with chromosome 7 alterations (7- and 7q-) had lower expression of POT1 versus 38% of diploid patients, 35% of 5q patients, and 42% of patients with other cytogenetic alterations (p=0.001). ANOVA testing indicated that expression of POT1 was significantly downregulated (less than 50% of control) only in patients with chromosome 7 alteration (p<0.000) but not in other cytogenetic subsets.

When we compared the survival of patients with POT1 downregulation to other groups, we observed a strong tendency toward shorter overall survival in patients with POT1 downregulation (median OS of 37 months [95% CI: 21-52] vs 53 months [95%CI: 30-75]; p=0.139). This tendency toward poorer OS was also observed when we excluded cases with chromosome 7 alterations (37 months [95% CI: 17-57] vs 53 months [95%CI: 25-80]; p=0.186).

Next, we evaluated the potential impact of POT1 expression on responses to therapies. In the subgroup of patients with available treatment records for analysis (n=58), a total of 42 patients received hypomethylating agents (HMA), and 47% of them achieved responses. When comparing POT1 expression levels to HMA response, we observed significantly lower POT1 expression in HMA non-responders than in responders (U Mann-Whitney test p= 0.028). In a regression model for response to HMA, we also observed that downregulation of POT1 was associated with a poorer response to HMA (OR 4.96 [1.01-24.37]; p=0.049). However, when we introduced chromosome 7 alterations into the model, POT1 expression lost its effect, which suggests that the impact of POT1 on response to HMA is due to its interaction with chromosome 7 alterations.

Taken together, the results of this study indicate that the downregulation of POT1 gene expression, which is related to chromosome 7 deletions, may play a role in the pathogenesis and prognosis of MDS, including response to HMA-based therapies.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.