BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.

B-cell lymphoma 6 (BCL6) is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with a BCL6 inhibitor revealed induction of BCL6-repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitors induced apoptosis and decreased colony-forming capacity, which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in a significant reduction of leukemia-initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal hematopoietic stem cells. Treatment with cytarabine further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to cytarabine. Treatment of AML patient-derived xenografts with BCL6 inhibitor plus cytarabine suggested enhanced antileukemia activity with this combination. Hence, pharmacologic inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.

Cancer-associated fibroblasts suppress SOX2-induced dysplasia in a lung squamous cancer coculture.

Tumorigenesis depends on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. While oncogenic drivers in lung squamous carcinoma (LUSC) have been described, the role of stroma in modulating tissue architecture, particularly cell polarity, remains unclear. Here, we report the establishment of a 3D coculture system of LUSC epithelial cells with cancer-associated fibroblasts (CAFs) and extracellular matrix that together capture key components of the tumor microenvironment (TME). Single LUSC epithelial cells develop into acinar-like structures with 0.02% efficiency, and addition of CAFs provides proper tumor-stromal interactions within an appropriate 3D architectural context. Using this model, we recapitulate key pathological changes during tumorigenesis, from hyperplasia to dysplasia and eventually invasion, in malignant LUSC spheroids that undergo phenotypic switching in response to cell intrinsic and extrinsic changes. Overexpression of SOX2 is sufficient to mediate the transition from hyperplasia to dysplasia in LUSC spheroids, while the presence of CAFs makes them invasive. Unexpectedly, CAFs suppress the activity of high SOX2 levels, restore hyperplasia, and enhance the formation of acinar-like structures. Taken together, these observations suggest that stromal factors can override cell intrinsic oncogenic changes in determining the disease phenotype, thus providing fundamental evidence for the existence of dynamic reciprocity between the nucleus and the TME of LUSC.

Benefits of Autologous Stem Cell Transplantation for Elderly Myeloma Patients in the Last Quarter of Life.

Although survival outcomes have improved dramatically over the last few decades in newly diagnosed myeloma patients, elderly patients have not yielded the same magnitude of benefit as evidenced by higher rates of reported myeloma-related deaths in patients over the age of 75. This is of particular importance given this cohort comprises a large proportion of myeloma patients with the median age of diagnosis being 70 years. One contributor to this discrepancy is reduced use of high-dose therapy and autologous stem cell transplantation (HDT/ASCT) in this population because of concerns for increased toxicity and safety. The objective of this retrospective analysis is to evaluate survival and safety outcomes in 53 newly diagnosed patients ≥74 years of age who underwent HDT/ASCT at our institution in comparison to 122 control patients in the same age bracket who did not undergo stem cell transplantation during this same time period. Patients treated at our institution were identified in our institutional myeloma database by age. They were all treated between November 2006 and October 2016 at the Winship Cancer Institute of Emory University. Fifty-three patients were identified who had undergone HDT/ASCT, and, to assess the relative benefit of ASCT, 122 control patients in the same age range were also identified who did not undergo HDT/ASCT during the same time period. The median age for the entire cohort was 77 years (74 years in the ASCT group versus 78 in the non-ASCT group). Median time to ASCT was 6 months (range 2-57 months). There were no gender or race differences between the 2 groups, although a higher proportion of high-risk patients underwent HDT/ASCT. Ninety-three percent of ASCT patients received triplet induction therapy with a proteasome inhibitor and immunomodulatory agent backbone in comparison to only 55% of patients the non-ASCT group. The median progression-free survival (PFS) for the ASCT group was 50 months versus 30 months in the non-ASCT group. The median overall survival (OS) was 80 months versus 40 months, respectively. In high-risk patients, the median PFS was 60.8 months, and the median OS was 77.8 months in the ASCT group compared to 26 months and 38 months in the non-ASCT group, respectively. There were no transplant-related deaths within the first 100 days in the ASCT group. This study offers real-world perspective and data on the safety and survival benefit of ASCT in the elderly population with a near doubling of OS when compared to those treated with similar regimens and modern agents without ASCT. These data provide a rationale for offering ASCT in elderly patients pending a thorough pretransplantation evaluation.

Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma.

UNLABELLED: Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs. SIGNIFICANCE: The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL.