A senescence stress secretome is a hallmark of therapy-related myeloid neoplasm stromal tissue occurring soon after cytotoxic exposure

Abstract

Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and β-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

“…The WHO has grouped t-MN with secondary MN and renamed it as “myeloid neoplasm post cytotoxic therapy”, with the assertion that a majority of MDS and AML occurring post-cytotoxic therapy have TP53 mut and that only multi-hit TP53 mut had a poorer outcome compared to single-hit [ 2 , 18 ], thus undermining the poor prognosis of single-hit TP53 mut t-MN. Exclusion of single-hit TP53 mut t-MDS from the TP53 mutated MDS have huge impact on management such as consideration for allogeneic stem cell transplantation [ 34 ], and exclusion from clinical trials targeted toward TP53 mut MDS. For example, allogeneic SCT may not be offered to fit single-hit TP53 mut t-MDS with BM blast 5–9% (according to ICC) and <20% (according to WHO) as they are considered to have OS similar to TP53 wt MDS.…”

The immunome of mobilized peripheral blood stem cells is predictive of long-term outcomes and therapy-related myeloid neoplasms in patients with multiple myeloma undergoing autologous stem cell transplant

“…Recently, a more nuanced model has emerged: a preleukemic clone may exist before the exposure to DNA-damaging therapies [ 59 ] and persist thereafter without manifesting as t-MN [ 60 ]. In addition, the role of non-HSC factors such as mesenchymal stromal cells has been described [ 61 ].…”

Senescent Stromal Cells in the Tumor Microenvironment: Victims or Accomplices?

“…Emerging evidence supports the role of senescent stromal cells as an accomplice in the growth of a variety of epithelial-derived solid tumors [ 52 , 99 , 100 ]. Similarly, recent studies have shown that senescent mesenchymal stromal cells contribute to the development of myeloid tumors [ 101 , 102 , 103 , 104 ]. The positive effect of the senescent stroma on tumor progression has been well established, but behind the scenes are the molecular mechanisms that link senescent stroma, cancer cells, and the TME.…”