SUMMARY Most adult stem cells, including hematopoietic stem cells (HSCs), are maintained in a quiescent or resting state in vivo. Quiescence is widely considered to be an essential protective mechanism for stem cells that minimizes endogenous stress caused by cellular respiration and DNA replication. Here, we demonstrate that HSC quiescence can also have detrimental effects. We found that HSCs have unique cell-intrinsic mechanisms ensuring their survival in response to ionizing irradiation (IR), which include enhanced pro-survival gene expression and strong activation of p53-mediated DNA damage response. We show that quiescent and proliferating HSCs are equally radioprotected but use different types of DNA repair mechanisms. We describe how nonhomologous end joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities. Our results demonstrate that quiescence is a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.
Using a mouse model recapitulating the main features of human chronic myelogenous leukemia (CML), we uncover the hierarchy of leukemic stem and progenitor cells contributing to disease pathogenesis. We refine the characterization of CML leukemic stem cells (LSCs) to the most immature long-term hematopoietic stem cells (LT-HSCs) and identify some important molecular deregulations underlying their aberrant behavior. We find that CML multipotent progenitors (MPPs) exhibit an aberrant B-lymphoid potential but are redirected towards the myeloid lineage by the action of the pro-inflammatory cytokine IL-6. We show that BCR/ABL activity controls Il-6 expression thereby establishing a paracrine feedback loop that sustains CML development. These results describe how pro-inflammatory tumor environment affects leukemic progenitor cell fate and contributes to CML pathogenesis.
Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are identification of likely responders to immunotherapy regimens among individuals with cancer or to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here the immune profiles of six murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to two immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative RT-PCR, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (Treg and MDSC), to analyze intratumoral and draining lymphoid tissues. Tumors stratified as highly or poorly immunogenic, with highly immunogenic tumors showing significantly greater presence of T-cell co-stimulatory molecules and immunosuppression in the tumor microenvironment. An absence of tumor-infiltrating CTL and mature DC was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine +/− DC vaccine immunotherapy was associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.
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