Apoptosis-promoted tumorigenesis: γ-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death

Abstract

Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in γ-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from γ-irradiation-induced death, because their glucocorticoid-mediated decimation in Puma-deficient mice activated cycling of stem/progenitor cells and restored thymic lymphomagenesis. Our demonstration that cycles of cell attrition and repopulation by stem/progenitor cells can drive tumorigenesis has parallels in human cancers, such as therapy-induced malignancies.

A fate worse than death: apoptosis as an oncogenic process

“…As the authors propose, PUMA mediated apoptosis of healthy cells could remove the competitive pressure that normally acts to restrain proliferation of aberrant cells, in doing so this leads to cancer. In support, glucocorticoid treatment eliminates cells in a PUMA-independent manner and leads to thymic lymphoma in PUMA-deficient mice 52 . Relating to our earlier discussion, particularly in liver cancer, apoptosis may also promote cancer by actively engaging compensatory proliferation of neighbouring cells 54 .…”

“…The BH3-only protein PUMA is essential for p53-mediated apoptosis in thymocytes and its loss enhances myc-induced lymphomagenesis [48][49][50][51] . Counter-intuitively, loss of PUMA prevents rather than promotes thymic lymphoma following irradiation 52,53 . Similarly, in a carcinogen-induced liver cancer model, deletion of PUMA or overexpression of anti-apoptotic BCL-2 protein also delays tumour development 54,55 .…”

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…Following exposure to 1.5 Gy γ-irradiation weekly for 4 weeks, mice typically succumb to thymic lymphoma around 150-200 days. In this experimental model, NOXA and BMF have been shown to suppress lymphoma development, 110,111 while the role of BAD remains contentious with one report describing accelerated thymic lymphomagenesis in BAD-deficient mice while another publication reported no effect. 54,55 Possible explanations for the discrepancy might include differences in γ-radiation dosing and schedule used or differences in genetic background (C57BL/6 55 versus complicated mixed background 54 ).…”

“…55 Remarkably, loss of PUMA completely abrogated γ-radiation-induced thymic lymphoma development. 111,112 This striking finding could be attributed to the profound resistance of PUMA-deficient white blood cells to DNA damage-induced apoptosis. The persistence of these cells obviated the need for mobilisation and burst of proliferation of haematopoietic stem/ progenitor cells that would normally occur to repopulate the depleted haematopoietic system, 111,112 a process that appears to be required for lymphoma development in this model.…”

“…111,112 This striking finding could be attributed to the profound resistance of PUMA-deficient white blood cells to DNA damage-induced apoptosis. The persistence of these cells obviated the need for mobilisation and burst of proliferation of haematopoietic stem/ progenitor cells that would normally occur to repopulate the depleted haematopoietic system, 111,112 a process that appears to be required for lymphoma development in this model. 109 These observations suggest that accumulation of DNA lesions, some of them potentially oncogenic, is not sufficient to induce tumour formation unless it is also accompanied by a drive for proliferative expansion of the mutation bearing leukaemia/lymphoma-initiating cells.…”