Preleukemia: one name, many meanings

Abstract

Definition of preleukemia has evolved. It was first used to describe the myelodysplastic syndrome (MDS) with a propensity to progress to acute myeloid leukemia (AML). Individuals with germline mutations of either RUNX1, CEBPA, or GATA2 can also be called as preleukemic because they have a markedly increased incidence of evolution into AML. Also, alkylating chemotherapy or radiation can cause MDS/preleukemia, which nearly always progress to AML. More recently, investigators noted that AML patients who achieved complete morphological remission after chemotherapy often have clonal hematopoiesis predominantly marked by either DNMT3A, TET2 or IDH1/2 mutations, which were also present at diagnosis of AML. This preleukemic clone represents involvement of an early hematopoietic stem cells, which is resistant to standard therapy. The same clonal hematopoietic mutations have been identified in older 'normal' individuals who have a modest increased risk of developing frank AML. These individuals have occasionally been said, probably inappropriately, to have a preleukemia clone. Our evolving understanding of the term preleukemia has occurred by advancing technology including studies of X chromosome inactivation, cytogenetics and more recently deep nucleotide sequencing.

Figure 1

Schematic diagram of the hematopoietic tree with stem cells having a preleukemic mutation (DNMT3A) and blast cells acquiring a Driver (pan-AML) mutation (NPM1 mutation), and retaining the DNMT3A mutations. Black dot, DNMT3A mutation; Red dot, NPM1 mutation. Figure summarizes data by John Dick's lab.

Figure 2

Evolution to MDS→secondary (s) AML (sAML)→remission and potential therapeutic intervention.

Figure 3

Hematopoiesis: Normal elderly individual±evolution to sAML. Normal elderly individuals can develop clonal hemtopoiesis marked by a mutation in their early hematopoietic stem cells (HSC). Some of these individuals will develop myelodysplastic syndrome (MDS); and with the acquisition of a Driver mutation, they can develop secondary AML (sAML). These patients may go into complete morphologic remission but often retain their preleukemic clone. With relapse, they can either retain the original Driver mutation or acquire a new Driver mutation. Dotted line suggests that some normal elderly individuals with clonal hematopoiesis may develop MDS and sAML.