Research overview

We are interrogating gene regulation in normal and malignant hematopoiesis.

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

Epigenetic regulation of cell fate specification

Red blood cell development and nuclear condensation

Anemia of myelodysplastic syndromes and bone marrow failure

Stem cell plasticity

Monosomy 7

Contiguous gene syndromes

Tumor suppressor genes

CRISPR/Cas9-based gene editing screens

CRISPR/Cas9-based modeling of aneuploidy

Collateral lethal treatment approaches

Therapy-related myeloid neoplasms

Clonal hematopoiesis

Chemoresistance

Differentiation therapy

Etiology of therapy-related myeloid neoplasms

Prevention strategies

Gene regulation in hematopoiesis

Single cell genomics

Epigenetics

Chromatin remodeling

Genome architecture

Transcription factor dosage

DNA damage response

Epigenetic regulation of DNA repair

Circumventing chemotherapy resistance

Collaborations with colleagues in method innovation

Synthetic lethality

Major approaches and models we commonly use.

AI – machine learning

Bioinformatics

Cell lines

Data mining

Functional genomics

Genetically-modified mouse models

Induced pluripotent stem cells

Primary human cells and patient samples

Proteomics

Lab members are encouraged to gain both wet lab and dry lab expertise.

Lab environment

Diverse and inclusive

Enthusiastic

Collaborative

Hard-working

Current collaborators

Kron lab

Drazer lab

Weber lab