A ‘telomere-associated secretory phenotype’ cooperates with BCR-ABL to drive malignant proliferation of leukemic cells

Abstract

Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout mice with critically short telomeres (CML-iG4) are growth retarded and proliferation is terminally stalled by a robust senescent cell cycle arrest. In sharp contrast, CML-like cells with pre-shortened, but not critically short telomere lengths (CML-G2) grew most rapidly and were found to express a specific 'telomere-associated secretory phenotype', comprising secretion of chemokines, interleukins and other growth factors, thereby potentiating oncogene-driven growth. Moreover, conditioned supernatant of CML-G2 cells markedly enhanced proliferation of CML-WT and pre-senescent CML-iG4 cells. Strikingly, a similar inflammatory mRNA expression pattern was found with disease progression from chronic phase to accelerated phase in CML patients. These findings demonstrate that telomere-induced senescence needs to be bypassed by leukemic cells in order to progress to blast crisis and provide a novel mechanism by which telomere shortening may contribute to disease evolution in CML.

Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes

“…Telomere dysfunction occurs when abnormally short telomeres fail to induce senescence and is an early hallmark of human cancer. Cells with telomere dysfunction are also known to secrete distinct types of inflammatory cytokines (5,6), but how telomeres are linked to this phenotype is not well characterized.…”

Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion

“…The p210 BcrAbl wildtype construct [20] was cloned into the γ-retroviral vector MP91-IRES-eGFP [21, 22] together with the eGFP marker. The BC32-construct as described in Thielecke et al [23] was introduced into the viral backbone by Gibson assembly [24].…”

Regulation of normal and leukemic stem cells through cytokine signaling and the microenvironment

“…Loss of functionality disrupts cytokine and hormone networks necessary to maintain the various hematopoietic lineages [46,47]. Because HSCs depend on adequate signaling from the bone marrow for proper quiescence and self-renewal, the age-related decline of immune function is often a trigger for leukemic transformation [48]. Cellular senescence increases chronic inflammation through the senescenceassociated secretory phenotype (SASP).…”