Proyectos por año
Detalles del proyecto
Description
PROJECT DESCRIPTION
Our overall goals are to establish (i) whether the hijacking of emergency myelopoiesis (EM) pathways
represents a shared mechanism of leukemogenesis in the context of different leukemic and pre-leukemic muta-
tions, and (ii) whether such a shared mechanism links clonal evolution in AML with environmental inflammatory
changes in aging and disease development. Hematopoiesis is a demand-adapted system in which self-renewing
hematopoietic stem cells (HSC) and downstream hematopoietic stem and progenitor cells (HSPC) integrate
signals from their bone marrow (BM) environment to adapt blood production to the need of the organism. In
regenerative conditions, this results in the transient engagement of EM pathways before a return to homeostasis.
During leukemia development and aging, EM pathways are constitutively engaged, likely in response to envi-
ronmental inflammatory changes. It is now increasingly appreciated that EM pathway activation represents a
distinct trajectory of myeloid development, which depends on unique HSPC signaling states, transcriptional reg-
ulation, and cell behavior. Just as normal hematopoiesis is regulated by the epigenetic landscape of HSCs, acute
myeloid leukemia (AML) is a disease largely driven by epigenetic dysregulation, with mutations in epigenetic
modifiers like DNMT3a that are also found in age-related clonal hematopoiesis (ARCH). However, beyond HSCs,
little is known about the epigenetic regulation of HSPCs, or the role of inflammatory stress and EM pathway
activation in AML pathogenesis. Our objective is to determine how engagement of EM pathways contributes to
epigenetic dysregulations and AML development by promoting clonal evolution and emergence of leukemic stem
cells (LSC) from pre-leukemic HSCs. In Aim 1, we will use our newly established atlas of EM pathway activation
to establish core and AML-specific EM-associated programs in diverse leukemic and pre-leukemic models to
identify putative interactions between hematopoietic and stromal populations that regulate EM pathways. We will
search for shared regulatory mechanisms between AML progression models, explore how they relate to human
AML, and spatially map the tissue architecture of leukemic hematopoiesis. We will also investigate the epigenetic
consequences of EM activation in AML and determine how DNMT3a mutation affects EM pathway regulation
through extensive functional analyses. In Aim 2, we will use Dnmt3amut ARCH and Dnmt3amut:Flt3ITD AML pro-
gression mouse models together with state-of-the art CARLIN clonal/lineage tracking approaches, powerful in
vivo CRISPR/Cas9 functional screening, and several modalities of repeated EM pathway engagement in primary
human cells and humanized mouse models to probe the role of EM pathway activation in clonal competition
between normal and pre-leukemic HSCs, and test whether EM induction is sufficient to drive progression of pre-
leukemic HSPCs to AML transformation. Collectively, these approaches will provide a comprehensive assess-
ment of the role of EM in AML development and identify key regulatory nodes that could be exploited transla-
tionally to disrupt EM pathway activation and prevent disease progression in multiple subtypes of leukemia.
Estado | Activo |
---|---|
Fecha de inicio/Fecha fin | 7/1/24 → 6/30/25 |
Keywords
- Biotecnología
- Investigación sobre el cáncer
- Oncología
Huella digital
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Proyectos
- 1 Activo
-
Aging-related hematopoietic stem cell intrinsic and microenvironmental signals in AML transformation
Kousteni, S. S. (PI), Passegue, E. (CoPI), Rabadan, R. (CoPI) & Steidl, U. U. (CoPI)
9/13/24 → 8/31/25
Proyecto