Cancer and myeloid clonal evolution in the short telomere syndromes

Abstract

The short telomere syndromes are considered the most common premature aging disorders. Although studies in genetically modified cells and animal models have suggested telomere dysfunction may promote genome instability, only a minority of humans with inherited loss-of-function mutations in telomerase and related genes develop cancer. Solid tumors are overall rare, and the vast majority of cancers are bone marrow-derived with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprising three-quarter of cases. In contrast to young short telomere syndrome patients who develop aplastic anemia, MDS and AML are usually diagnosed in adults who have milder short telomere defects. Here, we dissect the mechanisms by which these two bone marrow failure states, aplastic anemia and MDS-AML, evolve in the setting of varying degrees of telomere shortening. We discuss the implications of these observations for patient care as well as for understanding the genetics and biology of age-related myeloid clonal evolution.

Figure 1.. Age-dependent phenotypes of the short telomere syndromes.

The four short telomere syndrome presentations are shown on a schematic telogram relative to the normal population percentiles. Each dot refers to an individual patient at the typical age at diagnosis. The gradient schemes below show the decreasing risk of aplastic anemia with age along with the concurrent increase in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) risk with age.

Figure 2.. Pie graph shows relative distribution of cancers of the most common non-cutaneous malignancies in the short telomere syndromes with their estimated respective percentages.

The most common solid tumors are listed.

Figure 3.. Short telomere MDS tends to be hypoplastic and hypoproliferative.

Low power (20X) photomicrographs of bone marrow biopsies from a young adult showing normocellular marrow, a short telomere patient with a hypocellular marrow from hypoplastic myelodysplastic syndrome (MDS), and an adult with a hypercellular marrow in a patient with hyperplastic MDS as labeled above. Hypoplastic MDS is rare in unselected populations but represents more than half of short telomere MDS cases [27]. Images generously provided by Dr. Amy S. Duffield of the Johns Hopkins Division of Hematopathology.

Figure 4.. Model for the evolution of aplastic anemia and clonal hematopoiesis in MDS-AML in the short telomere syndromes.

Short telomere syndrome aplastic anemia patients have shorter telomere length at birth. They are thus more prone to stem-progenitor cell dropout and eventual loss of clonal mutations that may arise under the pressure of telomere shortening and with age. In contrast, short telomere MDS-AML patients have relatively longer telomere length (albeit shorter than age-matched controls) and are predicted to sustain clonal events that may arise with stem cell dropout, especially as they age. This would ultimately be predicted to lead to an age-dependent increase in MDS-AML.