Hilde Schjerven, PhD

Assistant Adjunct Professor
Laboratory Medicine
+1 415 502-3553
Research Overview: 

Proper blood cell (hematopoietic) development is essential for life and is controlled by a fine-tuned regulatory network that is still incompletely understood. The critical importance of this is reflected in the wide range of diseases that can arise due to defects in the regulation of hematopoiesis, including immunodeficiency, autoimmunity and blood cell cancers.

The Schjerven lab studies normal and malignant immune cell development with a focus on transcriptional regulation, and the molecular mechanisms underlying how mutations in key regulatory factors can cause disease. The transcription factor Ikaros, encoded by the IKZF1 gene, is a major focus of ongoing work. Due to the many roles of Ikaros in blood cell development and function, the lab has several diverse and complementary research projects.  

Ongoing projects and research directions:

Hematopoietic development: We use mutant mouse models and multi-color flow cytometry to study how specific genes regulate the development of different immune cell lineages. Increased basic understanding of the normal development, function and activation of our immune system is important both in regards to immune-cell intrinsic malignancies, but also to the emerging field of immunotherapy.

Basic science: We are also interested in basic science questions, and are fortunate to be able to study this in models with relevance to human disease. Our focus is on transcriptional regulation, and includes developmentally regulated alternative splicing and regulation of chromatin, and the functional role of this in hematopoiesis and blood cell malignancies.    

Autoimmunity is a disease of unknown etiology, but it is believed to be due to a combination of environmental factors and genetic predispositions. We study the role of one specific gene regulatory factor that has recently been associated with human autoimmune disease. Our current focus is how mutations in this gene can lead to break of B-cell tolerance, and we utilize transcriptome profiling and functional assays to elucidate the underlying molecular mechanisms.   

Leukemia is cancer of developing blood cells and is characterized into subtypes based on the cell lineage of origin (lymphoid vs myeloid) as well as defined oncogenic lesions. In most instances, an oncogenic mutation or translocation alone is not sufficient to lead to leukemic transformation. The pre-leukemic cell depends upon ‘a second hit’ (or multiple mutations) which often are mutations in regulatory factors acting as tumor suppressors. In addition, the leukemic cells are dependent upon, and interact with their in vivo microenvironment, adapting to and also influencing the healthy cells of the host. We study tumor suppressor function in both pre-B ALL and AML, with the overall aim of facilitating personalized medicine and development of new targeted therapeutics based on an increased understanding of the molecular mechanisms underlying the different subtypes of leukemia.

Non-coding RNA: We have recently embarked on studies of non-coding RNA and their role in normal and malignant blood cell development and function. This research direction emerged when we found that a key developmental regulatory factor and tumor suppressor in leukemia, regulated the expression of a set of non-coding RNA. Non-coding RNA is a pioneering field, where the many biological functions of these RNA molecules are just starting to be unraveled.

Methods and Approach: In addition to classical molecular biology, cell culture and immunological techniques, we also utilize complex and state-of-the-art tools to address our biological questions. This includes mutant mouse models for in vivo or ex vivo studies, multi-parameter flow cytometry and FACS sorting, genome-wide profiling by next-generation sequencing (RNA-Seq, ATAC-Seq, ChIP-Seq) and gene manipulation by CRISPR/Cas9 or cutting edge dCas9-mediated CRISPRi and CRISPRa. We welcome collaborations and adaptations of new methods that can help us address our biological questions.

Primary Thematic Area: 
Immunology
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Normal and malignant blood cell development, including break of immune tolerance (autoimmunity) and blood cell cancer (leukemia), with a focus on transcriptional regulation.

Websites

Featured Publications: 

A kindred with Mutant IKAROS and autoimmunity.

The Journal of allergy and clinical immunology

Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA, Dooley J, Schlenner S, van der Burg M, Verhoeyen E, Gijsbers R, Frietze S, Schjerven H, Meyts I, Claessens F, Humblet-Baron S, Wouters C, Liston A

Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre-B ALL.

The Journal of experimental medicine

Schjerven H, Ayongaba EF, Aghajanirefah A, McLaughlin J, Cheng D, Geng H, Boyd JR, Eggesbø LM, Lindeman I, Heath JL, Park E, Witte ON, Smale ST, Frietze S, Müschen M

Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros.

Nature immunology

Schjerven H, McLaughlin J, Arenzana TL, Frietze S, Cheng D, Wadsworth SE, Lawson GW, Bensinger SJ, Farnham PJ, Witte ON, Smale ST