HICCC Researchers Present at ASH Annual Meeting

Researchers from the Herbert Irving Comprehensive Cancer Center (HICCC) presented exciting new findings in hematologic malignancies at this year's American Society of Hematology (ASH) annual meeting, held December 9-12 in San Diego, CA. Each year, physicians and scientists from across the globe converge at the ASH annual meeting to share the latest advances in hematology/oncology. Below are a few highlights from the HICCC at ASH 2023.

Seda Tolu, MD, Wins Young Investigator Award

Since 2003, the Cutaneous Lymphoma Foundation has granted Young Investigator Awards to new physicians and scientists in the field of cutaneous lymphoma research. This year’s ASH Young Investigator Award went to Seda Tolu, MD, hematology/oncology fellow at Columbia/NewYork-Prebysterian, for her presentation at ASH “Outcomes in Minorities with PTCL by Clinical Trial Exposure.”

Synergy of Stag2-Cohesin Loss Results in Expansion of Npm1c-Mutant Hematopoietic Stem and Progenitor Cells

The stag2 gene is found in various types of cancers and is part of the cohesin complex—a protein ring that organizes the six feet of DNA present in every cell. Mutations in Stag2 and other parts of the cohesin complex disrupt DNA’s structure and interfere with the way genes are turned on and off within cells.

In this session, Jane Xu shared findings from the Viny lab demonstrating that loss of Stag2-cohesin functionally impacts the dynamics of Npm1c mutated hematopoietic stem and progenitor cells. These leukemia-initiating populations have an altered chromatin profile which may cause differential response to current and emerging therapies against Npm1c leukemia. The Viny lab is actively investigating the consequences of the epigenetic changes associated with Stag2-cohesin loss and testing various therapies using their pre-clinical model.

BTG2 Super-Enhancer Mutations Disrupt TFAP4 Binding and Deregulate BTG2 Expression in Diffuse Large B-Cell Lymphoma

The Pasqualucci and Dalla-Favera lab recently identified a pervasive hypermutation activity that hijacks super-enhancers in diffuse large B cell lymphoma (DLBCL) and showed that mutations in these regulatory DNA elements promote malignant transformation by deregulating the expression of several lymphoma driver genes (Bal et al., Nature 2022). The work presented by Pantaleo deSimone elucidated how a novel mutation frequently found in the super-enhancer of the BTG2 gene contributes to lymphoma development by allowing BTG2 to escape from negative regulation by the transcription factor AP4, which in turn facilitates the disruption of programs important for cell fate decisions.

These findings have important implications for the understanding of lymphoma biology and reveal a new pathway that could be exploited for therapeutic targeting in DLBCL. The long-term goal of the Pasqualucci lab is to elucidate the role of super-enhancer mutations in driving lymphomagenesis in vivo, as a means to improve the classification of DLBCL and to identify new targets for therapy in this disease.

Role of the S1P Signaling Pathway in the Pathogenesis of Angioimmunoblastic T-Cell Lymphoma

This study from the Palomero lab uncovered an important role of sphingosine-1-phosphate receptor 1 (S1P1) in the pathogenesis of an aggressive type of lymphoma called angioimmunoblastic T-cell lymphoma (AITL). Targeting the S1P pathway with FTY720, an FDA-approved drug for treating multiple sclerosis, significantly reduced lymphoma burden in the preclinical models. In her presentation, Wen-Hsuan Wendy Lin, MD, PhD shared findings demonstrating that S1P1 is overexpressed in primary samples of AITL patients, which could point to a novel role for S1P1 as a therapeutic target in AITL. Future directions of the work include elucidating molecular mechanisms leading to S1P1 activation in AITL, and translating findings into an early phase I clinical trial.

Reduced Early Mortality with Daratumumab-Based Frontline Therapy in Systemic AL Amyloidosis- Experience from the Columbia Amyloidosis Multidisciplinary Program

Early mortality has dramatically decreased in patients with AL amyloidosis in the era of Dara-VCD frontline therapy. However, there is still room for improvement in patients with stage IIIb disease, and data are lacking on hematologic and cardiac organ response rate and estimated early mortality in different stages.

In this session, Rajshekhar Chakraborty, MD, presented findings from a retrospective analysis of patients treated with daratumumab-based combination therapy at Columbia Amyloidosis Multidisciplinary Program (CAMP). The researchers found that despite a sicker population with more advanced cardiac involvement, daratumumab-based frontline induction therapy led to similar Heme-CR rate and favorable cardiac organ response rate. Additionally, the estimated 6-month early mortality was decreased by approximately 3-fold compared to historical data.