Kurre Lab Research Overview

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The Kurre laboratory has longstanding expertise in hematopoietic stem cell biology. In models of both acquired and inherited bone marrow failure, the lab team looks to make fundamental discoveries that improve understanding of how bone marrow stem cells are regulated. The Kurre lab’s work emphasizes preclinical development of new therapeutic strategies. Collaborations at CHOP, with investigators at the University of Pennsylvania and labs elsewhere in the US, provide access to a range of state-of-the-art experimental tools and approaches.

A growing lab team is working on three lines of investigation:

  • Mechanisms of hematopoietic failure during fetal development
  • Preclinical stem cell gene therapy for Fanconi Anemia
  • MiRNA regulation of hematopoietic stem cells in the leukemia microenvironment

Hematopoietic stem cells (HSC) are coordinately regulated through integration of intrinsic programs and extrinsic cues. Highly specialized bone marrow microenvironments (“niches”) provide the signals that support self-renewal and differentiation to maintain homeostatic lifelong function or respond to regenerative demands following injury. While adhesive interaction with niche components and cytokine support have been extensively studied, much less is known about the role of small vesicular structures, termed extracellular vesicles, that traffic between cells.

Acute myeloid leukemia (AML), a hematologic cancer that originates with mutations in hematopoietic stem cells, successively spreads through the bone marrow and constrains healthy hematopoietic cells. The active crosstalk at the root of stem cell attrition involves the trafficking of non-coding RNA from leukemia to stem cells.

The Kurre lab investigates fundamental aspects of vesicle trafficking in the bone marrow and the contribution to exhaustion of hematopoietic stem cells in the AML bone marrow. Relying on both congenic and xenogeneic murine models, the research team focuses on the mechanism by which EV- contained miRNA reach and regulate their targets as well as the consequences for regulation of the bone marrow compartment.

Related Publications

Abdelhamed S, Butler JT, Doron B, Halse A, Nemecek E, Wilmarth PA, Marks DL, Chang BH, Horton T, Kurre P. Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche. EMBO Reports. 2019. Jul;20(7). PMID: 31267709

Doron B, Abdelhamed S, Butler JT, Hashmi SK, Horton TM, Kurre P. Transmissible ER stress reconfigures the AML bone marrow compartment. Leukemia. 2018. Apr;33(4):918-930. PMID: 30206307

Hornick N, Doron B, Abdelhamed S, Huan J, Harrington C, Shen R, Cambronne X, Verghese S, Kurre P. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Science Signaling. 2016. Sep 6;9(444). PMID: 27601730

Jianya Huan J, Hornick N, Goloviznina N, Kamimae-Lanning A, David L, Wilmarth P,  Mori T, Chevillet J, Narla A,  Roberts C,  Loriaux M, Chang B, Kurre P. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia. Dec;29(12):2285-95. PMID: 26108689.

Fanconi Anemia (FA) is a rare, recessively inherited disorder with prominent cancer predisposition and progressive failure of the bone marrow to supply adequate blood cells. Patients typically present in early school age with signs of bone marrow failure. The genetic defect in any one of the 22 FA genes identified so far impacts DNA repair and integrity of the hematopoietic stem cells (HSC) pool. While HSC in both patients and mice are rapidly lost to apoptosis early in life, neither the origin nor the mechanism of spontaneous HSC failure have been identified. As a result, stem cell transplantation from an HLA-matched healthy donor is currently the only curative treatment option.

The Kurre lab team recently demonstrated that mice with a germline defect in a gene encoding for proteins involved in the FA DNA repair pathway first show deficits in utero, when HSC fail to expand adequately. Unlike mouse models of postnatal hematopoietic failure in FA, this phenotype is unprovoked, and it coincides with the rapid expansion of the HSC pool in the fetal liver. Understanding how fetal deficits emerge, and identifying ways to ameliorate those losses, promises much needed scientific insight and holds significant translational potential.

The Kurre lab team collaboratively investigates the fundamental aspects of stalled replication and cell cycle arrest that lead to hematopoietic failure. Moreover, the lab’s data suggest that the lack of expansion may link oligoclonality to genetic instability and potentially inform the risk of malignant evolution in FA.

Related Publications

Kurre P. Hematopoietic development: a gap in our understanding of inherited bone marrow failure. Exp Hematol. 2018. Mar;59:1-8. PMID: 29248612

Yoon YM, Storm K, Kamimae-Lanning A, Goloviznina N, Kurre P. Endogenous DNA damage leads to P53-independent deficits in replicative fitness in fetal murine Fancd2-/- hematopoietic stem and progenitor cells. Stem Cell Reports. 2016. Nov 8;7(5):840-853. PMID 27720904

Kamimae-Lanning A, Goloviznina N, Kurre P. Fetal origins of hematopoietic failure in a murine model of Fanconi Anemia. Blood. 2013. 121(11):2008-12. PMID: 23315168

Disorders arising from inherited mutations in hematopoietic stem cells (HSC) can result in partial or complete loss of blood and immune cell production. The defects underlying these disorders often compromise core cellular functions and many confer loss of HSC self-renewal. Research over the past decade revealed the specific genetic basis for several of these disorders. At the same time, the scientists in this field developed strategies to deliver genes to genetically complement and phenotypically correct those defects in HSC. Fanconi anemia (FA) is a rare bone marrow failure disorder that manifests clinically by early school age. While genetically complex, with patients inheriting compound heterozygous mutations in any one of 23 genes, the resulting defect in all cases disables DNA repair. Complementation with the proper genetic sequence can reverse this stem cell phenotype, and clinical studies now suggest that this may become a cure for patients. A remaining obstacle is the vulnerability of FA HSC to manipulation and the resulting number of successfully corrected HSC available to provide for lifelong function.

The Kurre lab has long studied preclinical approaches to maximize efficiency of viral vector delivery while minimizing stem cell losses. The team currently is investigating strategies for the direct delivery to the HSC niche in the bone marrow as a way to preserve sufficient HSC numbers and clonal diversity in FA.

Related Publications

Chakkaramakkil SC, Goloviznina NA, Skinner AM, Lipps HJ, Kurre P. S/MAR sequence confers long-term mitotic stability on non-integrating lentiviral vector episomes without Selection. Nucleic Acids Research. 2014. Apr;42(7):e53. PMID: 24474068.

Kurre P, Anandakumar P, Kiem HP. Rapid 1-hour transduction of whole bone marrow leads to long-term repopulation of murine recipients with lentivirus modified hematopoietic stem cells. Gene Therapy. 2006. Feb;13(4):369-73. PMID: 16208421

Kurre P, Anandakumar P, Harkey MA, Thomasson B, Kiem HP. Efficient marking of murine long-term repopulating stem cells targeting unseparated marrow cells at low lentiviral vector particle concentration. Mol Ther. 2004. Jun;9(6):914-22. PMID:15194058

Nearly half of all patients diagnosed with acute myeloid leukemia (AML) face disease recurrence after initially successful induction therapy. Persistent disease and clonal selection compromise subsequent treatment and patient survival. Mechanisms of resistance are diverse, ranging from cell intrinsic to those specified by adaptation of the leukemic microenvironment, i.e. extrinsic.

The Kurre lab team reported the involvement of extracellular vesicles (EVs) in the compartmental remodeling that accompanies AML invasion of the bone marrow. Studies in mouse models and patient-derived samples revealed widespread induction of endoplasmic reticulum (ER) stress in AML blast cells that was transferred to the stroma.

This project will pursue the observation of ER stress transmission to the BM stroma (already a known mechanism of drug resistance in the solid tumor microenvironment) and determine how ER stress transfer to stroma confers functional chemoresistance and protects AML cells from eradication by chemotherapy. What are the compartmental and systemic consequences of ER stress? How does ER stress relate to conventional measures of innate immunity? Can inhibition of unfolded protein response ameliorate drug resistance?

Recent studies by the Kurre lab team and others have identified the origins of hematopoietic failure in Fanconi Anemia (FA) during development. In a series of experiments, the lab team identified midgestation as a critical window for the onset of hematopoietic stem cells deficits in FA mice, and replication stress as the underlying mechanism. In this project, the Kurre lab team will delve into the molecular and cellular underpinnings of this observation and focus on the functional implications of fetal HSC.

Relevant question include: What is the relationship between checkpoint activity, genetic instability, and hematologic malignancy in FA HSC? How do clonality and hematopoietic reserve impact the kinetics of bone marrow failure? Can the fetal HSC phenotype be rescued early postnatally?

Insights from these experiments will help the Kurre lab to develop rational approaches to pharmacological reversal of the fetal block in HSC expansion. These studies will leverage new FA animal models, drug discovery, and involve studies of genome stability.