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Role of ERK isoforms in normal hematopoiesis and leukemia

Mitchell Geer

Mitchell Geer


New York University School of Medicine

Project Term: July 1, 2019 - June 30, 2022

Current therapies for cancers driven by “RAS/ERK’ pathway mutations, such as juvenile myelomonocytic leukemia (JMML), are either high risk (bone marrow transplant) or ineffective (targeted inhibitors). We have identified a unique dependency of JMML cell growth for a group of ERK targets, which are not required for normal blood cell growth. We are investigating this further and aim to identify the ERK targets responsible, which may provide new drug targets to treat JMML and other cancers.

Lay Abstract

It is estimated that around 500 billion mature blood cells are produced every day. These cells originate from a small number of hematopoietic stem cells (HSCs) that give rise successively to various “progenitors” for red blood cells, platelets and different types of white blood cells. Progenitors expand to a well-controlled number and then produce mature blood cells. Under healthy conditions, circulating numbers of blood cells are kept within narrow ranges. HSCs and progenitors must receive and process signals in order to maintain this blood population. These signals include soluble proteins that bind to receptors on the surface of cells. When bound, receptors activate a cascade of signaling events within the cell, ultimately resulting in changes in gene expression and cell behavior. Not surprisingly, mutations that affect these complex processes can—and do—give rise to blood cancers. One of the most common signaling cascades in cells is the so-called “RAS/ERK” pathway. Mutations that hyperactivate this pathway contribute to more than 30% of human cancers, including many hematological malignancies. For example, over 80% of Juvenile Myelomonocytic Leukemia (JMML) patients have RAS/ERK pathway mutations. JMML is a rapidly developing leukemia of young children, with a median survival of only one year. The only curative treatment is stem cell transplant, which carries a high risk and is often unsuccessful at preventing recurrence of the leukemia. It is therefore essential to better understand the mechanisms driving JMML, in order to identify improved therapies. RAS/ERK signaling has been well characterized up to ERK1 and ERK2, at which point the pathway branches to over 300 known or suspected targets (“substrates”). These substrates fall into two major groups, defined by their ability to interact with the DBP- or CD-domains of ERK1 and ERK2. These two domains can be mutated individually, allowing their functions to be separated. Our lab has shown that normal blood progenitor cells can grow when either of these domains are mutated in ERK1 or ERK2. However, progenitors co-expressing a cancer-causing mutation fail to proliferate when the DBP-domain of ERK1 is mutated. Therefore, we hypothesize that signaling pathways within leukemic cells are rewired, such that they become dependent upon one or more ERK1 DBP-binding substrates. My goal is to identifying these substrate(s), as targeting these proteins might selectively kill leukemic cells in JMML or other RAS/ERK-driven blood disorders.

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