Ann Mullally

All Publications

• Whole-genome CRISPR screening identifies N-glycosylation as a genetic and therapeutic vulnerability in CALR-mutant MPN. Blood Jutzi, J. S., Marneth, A. E., Ciboddo, M., Guerra-Moreno, A., Jiménez-Santos, M. J., Kosmidou, A., Dressman, J. W., Liang, H., Hamel, R. S., Lozano, P. R., Rumi, E., Doench, J., Gotlib, J. R., Krishnan, A., Elf, S., Al-Shahrour, F., Mullally, A. 2022

  Abstract

  Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPN). Although the biological mechanism by which CALR mutations cause MPN has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPN. To identify unique genetic dependencies in CALR-mutant MPN, we performed a whole-genome CRISPR knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (amongst others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor, 2-deoxy-glucose (2-DG), and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared to wild-type cells, and normalization of key MPN disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow, as compared to bone marrow-derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPN.

  View details for DOI 10.1182/blood.2022015629

  View details for PubMedID 35763665

• Whole-Genome CRISPR Screening Identifies N-Glycosylation As an Essential Pathway and a Potential Novel Therapeutic Target in CALR-Mutant MPN Marneth, A., Jutzi, J. S., Guerra-Moreno, A., Ciboddo, M., Jimemez Santos, M., Kosmidou, A., Hamel, R., Lozano, P., Rumi, E., Doench, J. G., Gotlib, J., Krishnan, A., Elf, S., Al-Shahrour, F., Mullally, A. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-149218

  View details for Web of Science ID 000736398800058

• Physiological Jak2V617F Expression Causes a Lethal Myeloproliferative Neoplasm with Differential Effects on Hematopoietic Stem and Progenitor Cells CANCER CELL Mullally, A., Lane, S. W., Ball, B., Megerdichian, C., Okabe, R., Al-Shahrour, F., Paktinat, M., Haydu, J. E., Housman, E., Lord, A. M., Wernig, G., Kharas, M. G., Mercher, T., Kutok, J. L., Gilliland, D. G., Ebert, B. L. 2010; 17 (6): 584-596

  Abstract

  We report a Jak2V617F knockin mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild-type HSCs. In contrast, myeloid progenitor populations are expanded and skewed toward the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to JAK2V617F-positive MPN.

  View details for DOI 10.1016/j.ccr.2010.05.015

  View details for Web of Science ID 000278952300010

  View details for PubMedID 20541703

  View details for PubMedCentralID PMC2909585