Biology subjects

Chavez, J. S.

Publications and source records attributed to Chavez, J. S..

3 recordsLinked to original sources

bioRxiv2021

PU.1 expression defines distinct functional activities in the phenotypic HSC compartment in a mouse model of inflammatory stress

The transcription factor PU.1 is a critical regulator of lineage fate in blood-forming hematopoietic stem cells (HSC). In response to inflammatory signals, PU.1 expression is increased in HSC, activating myeloid differentiation genes while repressing cell cycle and protein synthesis genes. To address potential functional heterogeneity arising in the phenotypic HSC compartment due to changes in PU.1 expression, here we fractionated phenotypic HSC using the SLAM code in conjunction with PU.1 expression levels using the PU.1-EYFP reporter mouse strain. While PU.1lo SLAM cells contain extensive long-term repopulating activity and a molecular signature corresponding to HSC activity at steady state, under inflammatory conditions the PU.1lo SLAM fraction is comprised almost entirely of HSC-like cells containing extensive short-term megakaryocytic potential. Our data demonstrate that the phenotypic HSC gate is heterogenous, and that similar PU.1 transcription factor levels can be tied to distinct functional activities under steady-state and inflammatory conditions.

cell biology↗

bioRxiv2020

Transcription factor PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Loss of hematopoietic stem cell (HSC) quiescence and resulting clonal expansion are common initiating events in the development of hematological malignancy. Likewise, chronic inflammation related to aging, disease and/or tissue damage is associated with leukemia progression, though its role in oncogenesis is not clearly defined. Here, we show that PU.1-dependent repression of protein synthesis and cell cycle genes in HSC enforces homeostatic protein synthesis levels and HSC quiescence in response to IL-1 stimulation. These genes are constitutively de-repressed in PU.1-deficient HSC, leading to activation of protein synthesis, loss of quiescence and aberrant expansion of HSC. Taken together, our data identify a mechanism whereby HSC regulate their cell cycle activity and pool size in response to chronic inflammatory stress.

immunology↗

bioRxiv2020

Chronic Interleukin-1 exposure triggers selective expansion of Cebpa-deficient multipotent hematopoietic progenitors

The early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1{beta} (IL-1{beta}), impacts Cebpa-deficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found that Cebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1{beta} exposure engendered potent selection for Cebpa loss. Chronic IL-1{beta} augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1{beta}, and competitively expand. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention. SummaryHiga et al. show that chronic interleukin-1{beta} exposure primes hematopoietic stem and progenitor cells for myelopoiesis by upregulating myeloid differentiation programs and repressing stem gene programs in a Cebpa-dependent manner. Consequently, interleukin-1 potently selects for Cebpa loss in hematopoietic stem and progenitor cells.

cancer biology↗