Our overarching goal is to improve the outcome for patients with myeloid neoplasms, particularly the high-risk subset unresponsive to current treatment protocols. In the last decade, the somatic mutations in myeloid malignancies have been well characterized. Many of these genetic changes impact tumor suppressor genes encoding transcription factors and epigenetic regulators. This presents a challenge for the field, as restoring the normal level or activity of an inactivated tumor suppressor gene has remained therapeutically elusive. Our lab is taking several different approaches to circumvent this problem in the context of -7/del(7q), a cytogenetic change present in half of high-risk myeloid neoplasms. CUX1 is a non-clustered homeobox transcription factor encoded on 7q and is recurrently mutated in hematopoietic and solid tumors. We reported that loss of CUX1 is sufficient to cause myeloid malignancies in mice. We are taking several approaches to identify druggable partners or pathways to target CUX1-deficient malignancies. In addition, we are identifying other tumor suppressor genes on 7q to understanding the molecular pathogenesis of 7q deletions and reveal new therapeutic vulnerabilities of chemoresistant disease.
In parallel, accomplishing this work will yield insight into several outstanding questions in developmental biology, cancer biology, and gene regulation. Our research program is investigating: i) transcriptional mis-regulation in cancer, and how transcription factor haploinsufficiency is interpreted at the cis-regulatory level; ii) the role of transcription factors in genome architecture and differentiation; iii) the probabilistic nature of stem cell fate determination; iv) chromatin remodeling in DNA repair; v) the contribution of en bloc genic haploinsufficiency due to large segmental deletions, ie. “contiguous gene syndromes” in cancer; and vi) how genetics and environmental exposures interact to promote cancer, with the goal of ultimately preventing this disease.
Ongoing and available projects in the lab
Hematopoietic stem cell regulation
Red blood cell development
Anemia of myelodysplastic syndromes and bone marrow failure
Contiguous gene syndrome of chromosome 7
Tumor suppressor genes
CRISPR/Cas9-based gene editing screens
Therapy-related myeloid neoplasms
Gene regulation in hematopoiesis
Preclinical drug studies
Collaborations with clinical colleagues in clinical trials
Major approaches and models we commonly use.
Primary human cells and patient samples
Diverse and inclusive