Response: Or both?

We appreciate the comment given by Jahrsdörfer and Weiner arguing for the hypothesis that short telomeres in CLL are a consequence, rather than a cause, of complex chromosomal aberrations.

In our paper¹  we referred to the so-called M1/M2 model, which originally was based on cell culture studies, and in the discussion we wrote that our data “can be interpreted as an accumulative effect of 2 main events: (1) genetic alterations force cells to bypass senescence (M1) leading to additional telomere attrition and (2) short telomeres induce genetic instability.”^1p2250 The genetic alterations leading to a bypass of M1 (senescence) are in CLL probably 11q− (ATM↓) and 17p− (p53↓).²  CLL cells with these aberrations in general have unmutated IGHV genes^3,4  and it can also be assumed that these cells from the start have shorter telomeres than B cells with mutated IGHV genes.^5,6  We also wrote “11q− or 17p− aberration in combination with overexpression of ZAP-70 and/or CD38 give cells a survival advantage and facilitate cell cycle progression, one consequence of which is telomere attrition.”^1p2250 In addition, we referred to the report showing a correlation between birth rate and disease activity,⁷  concluding that “[t]hese data suggest that cell kinetic characteristics can contribute to differences in telomere length.”^1p2250

In summary, we argue that short telomeres can be a consequence of certain genetic aberrations leading to increased cell proliferation, and thus agree with Jahrsdörfer and Weiner, but we also believe that it is likely that the cell of origin differs in telomere length depending on its IGHV gene status. Critically short telomeres can thereafter induce a state of genetic instability leading to further genetic alterations.

Regarding the question “Short telomeres in B-CLL: The chicken or the egg?” we argue that the answer rather is “both,” which means that the short telomere phenotype is the result of many interacting factors as outlined in our paper. The “chicken” is the telomere length in the cell of origin, and the “egg” includes a number of possible events (11p−/17p−, ZAP70↑, CD38↑, and others) with effects on cell cycle progression and survival.