Myelodysplastic Neoplasia

Tumor niche modulation and immune evasion are hallmarks of cancer that have added importance in elderly patients (such as those with MDS), where an aging immune system may contribute to the formation of a tumor-permissive microenvironment. We hypothesize that the immune microenvironment of MDS patients contributes to immune escape and uncontrolled expansion of aberrant hematopoietic cell clones and, therefore, therapeutic strategies that amplify the immune response could be of value in reducing the clonal and disease burden in MDS patients. 

The overall goal of this line of research is to elucidate how MDS cells escape immunosurveillance, with the ultimate goal of guiding the development of novel cellular or immune reprogramming therapies to prevent or slow MDS progression. To this end, we will study the identity, quantity and functionality of immune cells from healthy elderly patients and donors, as well as their interactions with tumor cells, and identify opportunities for immunological therapeutic intervention.

Objectives:

• Analysis of the identity and transcriptional status of immune niche cells in MDS.  
• Functional characterization of the immune repertoire in MDS.
• Assessment of the immunogenic capacity of MDS stem cells. 
• Identification and validation of new therapeutic targets for MDS. 

Several recent studies of MDS and AML hematopoietic stem cells have revealed that neoplastic stem cells can be found in two distinct differentiation stages, one more primitive and one more granulo-monocytic (GM), which give rise to two distinct hematopoietic hierarchies.

Each of these hierarchies has been associated with distinct genetic alterations. In addition, our findings, and those of other groups, suggest that stage of differentiation confers different drug sensitivity to neoplastic cells, but it is unclear whether this is directly dependent on mutation or cell identity. 

We hypothesize that the signaling pathways required for the expansion and survival of MDS stem cells with GM trajectories during disease initiation and progression are different from those required in cells with primitive trajectories. The overall objective of this line of research is to characterize GM hierarchies in MDS patients at different stages of the disease in order to identify targeted therapeutic targets. To this end, we will study trajectories at the single cell level in early and late stages of the disease, identifying aberrant stem cells and analyzing their specific oncogenic dependencies.

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Objectives:

• Transcriptomic characterization of GM hematopoietic hierarchies of MDS patients at diagnosis.  
• Discrimination of oncogenic mechanisms dependent on stem cell differentiation status from those dependent on specific mutations. 
• Identification of signaling pathways that regulate the survival and proliferation of MDS stem cells with GM trajectory during progression to AML. 
• Validation of new therapeutic targets for patients with MDS-GM.