Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

Abstract

In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner.

Stability of a delay system coupled to a differential-difference system describing the coexistence of ordinary and mutated hematopoietic stem cells

“…The proportion of cells which is always proliferating will be considered as an ultimate leukemic state, as motivated in the sequel. Indeed, in recent medical research, it has been proven that cancer cells appear after an accumulation of several mutations that occur almost entirely, and in a chronological order, in the stem cell compartment [14]. A first mutation in some genes encoding enzymes in epigenetics (TET2, DNMT3A, or other [7], [25]), will increase the self-renewing activity of the affected subpopulation of cells.…”

“…Finally, a subsequent mutation impairing proliferation control (e.g., of the Flt3-ITD type) will appear in a subpopulation of cells that have already encountered and accumulated one or more of the previous mutations ( Figure 1). This latter mutation activates an uncontrolled overproliferation of blasts and thereby causes acute myeloid leukemia [14]. More complex successions of mutational events may occur [27], however we will in the sequel have in mind a typical TET2/DNMT3A followed by NPM1 and finally Flt3-ITD sequence of mutations.…”

Analysis of a System Describing Proliferative-Quiescent Cell Dynamics

“…Therefore the condition (18) tells us that n(x, t) ≤ n 0 M and the definition (17) implies that E(t, x) remains convex all along the dynamics. Therefore the solution satisfies…”

“…In this representation, we do not consider the whole hematopoietic tree (as done in, e.g., [2,24]), but only its most immature components. Indeed, having in mind, as in [2,24], future applications to acute myeloid leukemia, that emerges from these early stages [17], we believe that this is the right place in the hematopoietic tree to set the relevant mathematical model and its analysis.…”

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

“…Preleukemic clones may survive chemotherapy and persist in AML patients during complete remission (CR). [2][3][4][5][6] Several groups have reported frequent persistence of DNMT3A mutations during CR, but found no association with AML relapse or survival. [7][8][9][10] In contrast, in another study analyzing a larger panel of genes in 50 AML patients, mutation persistence associated with shorter event-free and overall survival (OS).…”