Dissecting and Targeting Transcriptional and Epigenetic Regulation in Advanced Myelofibrosis
Thrive Award Spotlight :
Iannis Aifantis, PhD
“Our work has previously focused on other types of blood cancer, including myeloid and lymphoid leukemias,” says Iannis Aifantis, PhD, of NYU Langone. “A key aspect of the pathogenesis of myelofibrosis (MF) is the abnormal creation of blood outside the bone marrow,” for instance in the spleen. “Our work aims to understand at the molecular and single cell level the mechanisms of this (pathogenic) process and how we can target abnormal myeloid-biased blood creation.”
Dr. Aifantis’ interest in the blood cancer field was prompted by early research in which he focused on the development of the immune system, specifically T cells. “That brought me into the field of blood malignancies and made me focus both on cell intrinsic (specific on cancer cells) and extrinsic (interactions with the Immune system) mechanisms of leukemia initiation and progression,” he tells MPNRF.
Rebecca Austin, PhD, explains the MPNRF-funded project in its simplest terms. “In myelofibrosis, the bone marrow can no longer make healthy blood. In this case . . . the spleen tries to help . . . but it is inefficient and generates abnormal cells. To develop treatments for patients with myelofibrosis, it is important to understand how to reverse this process so that healthy blood can once again be made in the bone marrow.”
The cardinal feature of MF is progressive fibrosis of the bone marrow, which often leads to blood formation in the spleen (causing an enlarged spleen).
These studies show that blood formation in the spleen is biased toward the myeloid (related to the bone marrow) lineages and is therefore lacking normal blood cell formation.
The project focused on understanding the controlling factors for this bias and testing therapeutic approaches to counter it.
DETAILS: Myelofibrosis (MF) is a complex clonal hematopoietic malignancy with limited treatment options and propensity to transform to acute myeloid leukemia. The cardinal feature of MF is progressive fibrosis of the bone marrow (BM) leading to blood formation outside the BM and primarily in the spleen. Ultimately this can lead to low blood counts due to inefficient blood formation. In depth molecular analysis of blood formation in the spleen of MF patients has not be conducted. Preliminary studies of hematopoietic stem and progenitor cells (HSPCs) from myelofibrotic spleens and healthy BM revealed a differentiation bias for erythroid/megakaryocyte progenitors. These and other data led to the hypothesis that deregulated RNA splicing and epigenetic chromatin architecture