The Mullally laboratory is a translational oncology laboratory focused on the study of myeloid malignancies, primarily myeloproliferative neoplasms (MPN). We employ a range of experimental approaches including murine models, functional genomics and proteomics as well as classical cellular and molecular biology.
Functional and Molecular Dissection of Mutant Calreticulin in MPN
In 2013, somatic mutations in an endoplasmic reticulum chaperone, calreticulin (CALR) were identified in approximately 40% of patients with MPN using whole exome sequencing. The Mullally lab recently elucidated the mechanism by which mutant CALR is oncogenic and causes MPN. We found that the thrombopoietin receptor, MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation. We further demonstrated that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the mutant-specific C-terminus of the mutant protein and that mutant CALR physically interacts with MPL. We are currently working to understand additional aspects of mutant CALR biology and to develop novel strategies to therapeutically target mutant CALR in MPN.
Preferentially targeting disease-propagating MPN stem cells
The lab has extensive expertise with genetic murine models and hematopoietic stem cell (HSC) biology, having established and extensively characterized a murine model of the JAK2V617F mutation, the most common molecular abnormality in MPN. We have used this model to investigate the effects of JAK2 inhibitors and interferon therapy on MPN stem cells. More recently, we identified the DNA helicase, RECQL5 as a critical regulator of genome stability in MPN. We further demonstrated that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F-mutant cells through RECQL5-targeted synthetic lethality. This work offers the potential for the development of therapies to preferentially target JAK2V617F-mutant cells over normal hematopoietic cells for more effective anti-MPN therapy.
Leukemic transformation and hematopoietic-stromal interactions in MPN
The lab is also studying the genetic events that drive the transformation of MPN to acute myeloid leukemia (AML) with goal of developing improved therapeutic approaches for these leukemias, which are highly chemo-refractory. Other projects are focused on advancing the understanding of the biology of myelofibrosis, a subtype of MPN associated with a fibrotic bone marrow and on investigating the differential bone marrow niche interactions of MPN disease-propagating stem cells.
We are using next generation sequencing approaches to identify heritability alleles for MPN within families where more then one first-degree relative develops MPN.