Hematological Neoplasia

The Genetics of Hematologic Diseases

Many malignant hematologic diseases can be traced to mutations that spontaneously arise in blood stem cells.

The great majority of patients with one of the myeloproliferative neoplasms (MPNs) – myelofibrosis, essential thrombocythemia, or polycythemia vera – have an acquired mutation in blood stem cells in one of three genes: CALR, JAK2, or MPL. Specific mutations in these genes activate the JAK-STAT pathway. The JAK-STAT pathway is connected and downstream of the receptors of hematopoietic growth factors such as erythropoietin (EPO) and thrombopoietin (TPO) that drive the production of specific blood cells. JAK-STAT pathway activation characterizes the myeloproliferative neoplasms, in which there is an increase in peripheral blood cells. These mutations, however, do not explain these diseases fully. Other mutations and physiologic influences, some known, some yet to be discovered, contribute to the onset and clinical progression of the MPNs.

If one cell type were regarded as the seat of myelofibrosis, it is the megakaryocyte, the cell that makes platelets. Megakaryocytes make cytokines and growth factors, packaging them into platelets which enhance the immune response and promote wound healing at the sites of injury. Over-activation of the JAK-STAT pathway by mutations, however, results in the excess secretion of these factors both locally in the bone marrow niche and systemically. An excess of these factors contributes to the pathophysiologic picture of bone marrow remodeling, extramedullary hematopoiesis with splenomegaly, and symptoms such as fatigue and fevers.

LSD1 inhibition specifically targets megakaryocytes by preventing their maturation from progenitor cells as well reducing the production of factors in mature megakaryocytes.

Inhibition of LSD1 in animal models of MPN has demonstrated additional biological effects that Imago hopes translate to clinical benefits for patients. In mouse models of MPN disease (JAK-STAT activation), treatment with an LSD1 inhibitor showed reduced volumes of spleens and livers, lower inflammatory cytokines in plasma, a resorption of reticulin in bone marrow, liver and spleen, a reduction in the number of myeloid cells carrying the activating mutation, and, in one mouse model of MPN, prolonged survival with continuous dosing. All of these disease parameters are being measured in our current clinical trial (NCT03136185).

Hematologic Neoplasia


Imago BioSciences, Inc.
San Francisco, CA