Kousteni Lab

The bone marrow stromal niche is a critical regulator of the development of hematological myeloid malignancies acting as a permissive niche required for their emergence or progression. Such permissiveness can be enhanced by alterations in the function or structure of different stromal cell compartments driven by aging or as a result of genetic alterations or disease and can lead to MPN, MDS or AML. Mutations in the stromal microenvironment can also contribute to the transformation of normal and pre-malignant hematopoietic stem cells. Examples of such oncogenic signals include deletion of retinoic acid receptor gamma or retinoblastoma protein in stromal cells, a gain-of-function mutation in β-catenin in osteoblasts, deletion of Dicer1 in osteoblast progenitors, a Noonan syndrome causative mutation in PTPN11, and mutations in the ribosome biogenesis SBDS gene causative of the Schwachman-Diamond bone marrow failure syndrome in stromal cells. Our laboratory integrates genomic, transcriptomic and epigenetic approaches to understand MDS and AML pathogenesis in the context of the stromal niche. We perform molecular profiling of hematopoietic stem cell populations implementing MDS development and clonal outgrowth in AML transformation and determine how their interactions with specific niche populations affect transformation.

MDS and AML are clonal myeloid disorders characterized by impaired hematopoiesis resulting in cytopenia and in the case of AML excessive blast production. They present at all ages, but their incidence rates accelerate in the elderly, with a median age of diagnosis of ~70 years. MDS and AML can arise from a subset of already mutated pre-malignant hematopoietic stem cells that present in low frequency in otherwise healthy elderly individuals, a condition known as age-related clonal hematopoiesis (ARCH) . Interestingly, the most frequent of those mutations occur in genes encoding epigenetic regulators, such as DNMT3A, TET2 or ASXL1 which are also prevalent in MDS and AML. However, although such mutations occur frequently, they are only selected under specific conditions or require additional influences. Work from our group and others suggests that functional decline in aging blood-forming hematopoietic stem cells and signals from the aging niche that alter the transcriptional milieu or promote expansion of hematopoietic stem cell compartments have an impactful role in myeloid disease progression by promoting clonal expansion of mutated (pre-malignant) hematopoietic stem cells. We use genetic tools and single cell technology to integrate studies of clonal mutational evolution and niche components in patients and mouse models, to establish the mechanisms through which the aging marrow supports the outgrowth of MDS or AML initiating clones.

Cells in the bone marrow microenvironment influence MDS, MPN and AML outcome and resistance to treatment. Conversely, malignant myeloid cells can remodel the niche to their advantage, our laboratory is interested in identifying such mechanisms of stroma remodeling in MDS and AML. In particular, we have identified a niche-dependent, cell non-autonomous progression model for MDS and AML, in which malignant cells seize peripheral serotonin signaling in osteoblasts to promote their growth. This line of research leads to identification of molecules that mediate such interactions and act as oncometabolites marking MDS and AML development and disease progression from MDS to AML in patients.

Despite decades of effort, MDS and AML remain largely recalcitrant to targeted therapy. Recent exome sequencing projects in MDS and AML have identified spectra of mutations. Thus far, few of those have been amenable to targeted therapies. Furthermore, targeted therapies have been limited by the evolution of malignant subclones containing resistant mutations, prompting a search for alternative targets that may be more stable. Recognizing these limitations, our laboratory focuses on the MDS and AML microenvironment in the bone marrow that enables or sustains dysplastic cells. We have shown that activation of ß-catenin/Jagged1 signaling in osteoblasts in mice leads to MDS and progresses to AML. This pathway may sustain dysplastic hematopoiesis and progression to AML in a subset of MDS patients. More recently, we showed that a niche-dependent axis (kynurenine-HTR1B-SAA-IDO1) promotes MDS and AML growth. The finding that hematological malignancies can arise from the interaction between a normal cell and its defective environment enhances the potential for drug therapy: the osteoblast, or another type of stromal cell, in MDS and AML may be more amenable to drug therapy than the malignant cells since it lacks the propensity to mutate and clonally expand.