Clonal Hematopoiesis with Oncogenic Potential (CHOP): Separation from CHIP and Roads to AML

Abstract

The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome. These neoplasms may or may not transform to overt acute leukemia over time. Thus, depending on the type and number of somatic mutations, clonal hematopoiesis (CH) can be divided into CH with indeterminate potential (CHIP) and CH with oncogenic potential (CHOP). Whereas CHIP mutations per se usually create the molecular background of a neoplastic process, CHOP mutations are disease-related or even disease-specific lesions that trigger differentiation and/or proliferation of neoplastic cells. Over time, the acquisition of additional oncogenic events converts preleukemic neoplasms into secondary acute myeloid leukemia (sAML). In the present article, recent developments in the field are discussed with a focus on CHOP mutations that lead to distinct myeloid neoplasms, their role in disease evolution, and the impact of additional lesions that can drive a preleukemic neoplasm into sAML.

Keywords: cancer; clonal evolution; neoplastic stem cells; premalignant states.

Figure 1

Development and diversification of leukemic stem cells in secondary acute myeloid leukemia (sAML). Left panel, upper part: An initial oncogenic event transforms a normal stem cell into a premalignant (preleukemic) neoplastic stem cell (Pre-L-NSC) (blue boxes). These cells or their daughter cells acquire early somatic mutations. Usually, these have low oncogenic potential (blue-colored cells) and are thus slowly cycling or dormant cells so that the mutation is not detectable. After some time, more daughter clones develop and the somatic lesions may be detected and classified as clonal hematopoiesis with indeterminate potential (CHIP). After several years or decades, one or more daughter clones and their stem cells expand and may replace normal hematopoiesis. At that time, some of the stem cell clones may have acquired disease-specific oncogenic driver lesions (red-colored cells). Still, these cells may be indistinguishable from normal cells by morphology and in functional terms. In a next step, one or more of the sub-clones acquire additional driver mutations or lose tumor suppressor genes. As a result, the stem cells are now cycling and the neoplastic process forms a visible overt myeloid neoplasm (red-colored prominent clones—upper left panel). In most instances, these neoplasms still behave as indolent driver-positive neoplasm for some time. However, unless treated, many of these conditions will finally transform into a secondary acute myeloid leukemia (sAML). At that time, long-term disease propagating cells are called leukemic stem cells (LSC—red boxes). Note that all of the Pre-L-NSC-derived clones are also still present and can be detected (as small-sized sub-clones) in an overt sAML. Left lower panel: Nonspecific cytoreductive (palliative) therapy (example: hydroxyurea) can suppress the growth of cycling stem and progenitor cells for some time but cannot eradicate any of the Pre-L-NSC or LSC. After a variable (usually short) time period, a relapse develops. Right panel: Most interventional therapies (intensive chemotherapy, targeted drugs, or stem cell transplantation) are able to eradicate most or all of the LSC and their progeny, but not all Pre-L-NSC. When all LSC are killed, the patient enters complete remission and operational cure. In these patients, the Pre-L-NSC may or may not be detected as minimal residual disease. These Pre-L-NSC may (or may not) produce a late relapse after several months or years. Although some of the early mutations (rarely even drivers) of the original sAML clone may be detected in such relapsing disease, the molecular aberration profiles usually differ substantially from the initial molecular make-up of the sAML clone.

Figure 2

Major players contributing to the ‘oncogenic march’ in myeloid neoplasms. The genetic background may form the basis of a familiar predisposition to the development of hematopoietic (and thus also myeloid) neoplasms. In some of these families, more or less specific of even disease-related mutations (with low or even high oncogenic potential) are found. CHIP develops later during lifetime—the related somatic mutations per se (as isolated lesions) have a low oncogenic potential and are more frequently detectable at higher age. Therefore, these lesions are also called age-related clonal hematopoiesis (ARCH). Later, somatic mutations with CHOP may be acquired and usually lead to an overt myeloid neoplasm (at least after some time). This neoplasm may manifest as an indolent (chronic) myeloid neoplasm unless additional drivers (driver lesions) and other oncogenic hits (loss of tumor suppressors) are acquired. In a few cases, such additional driver lesions may be acquired in a CHIP status (blue triangle) or even a pre-CHIP status and may then lead to the immediate formation of primary (de novo) AML.