Convergent epigenetic evolution drives relapse in acute myeloid leukemia.

Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

Acute myeloid leukemia (or AML for short) is a type of blood cancer characterized by abnormally high production of immature white blood cells. Despite advances in AML treatment, many patients relapse after an initially successful first round of treatment. As a result, understanding the factors contributing to relapse is essential for developing effective treatments for the disease. Like most cancers, AML can evolve because of changes to the DNA sequence in cells that cause them to grow uncontrollably or resist treatment. Alongside these genetic mutations, AML cells also undergo 'epigenetic' changes, where regions of the DNA are modified and genes can be switched on or off without altering the DNA sequence. Previous research has demonstrated that epigenetic changes contribute to the development of AML, however, it was not clear if these changes could also make cells resistant to treatment without acquiring new DNA mutations. Nuno, Azizi et al. addressed this question by analyzing the epigenetic states of AML cells from 26 patients at the time of their diagnosis and after treatment when the disease had relapsed. Analysis revealed that almost half of the patients with AML experienced a relapse without acquiring new DNA mutations. Instead, these AML cells developed specific epigenetic changes that helped them to resist cancer treatment. Moreover, studying individual AML cells from different patients showed that the cells became more epigenetically similar at relapse, suggesting that they converge towards a more treatment-resistant disease. Future experiments will determine exactly how these epigenetic changes lead to treatment resistance. Currently, most of the drugs used to treat AML are either chemotherapies or ones that target specific DNA mutations. The findings of Nuno, Azizi et al. suggest that drugs targeting specific epigenetic changes may be more effective for some patients. Further studies will be needed to determine which patients may benefit and which epigenetic drugs could be useful.

Kinetics of CEA and CA15-3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC).

The aim of this retrospective analysis is to determine the correlation between tumour marker kinetics (TMK) like carcinoembryonic antigen (CEA) and/or cancer antigen (CA) 15-3 and imaging concerning effectiveness of chemotherapy in metastatic breast cancer (MBC) patients. TMK (CEA, AxSYM, Abbott; CA15-3, Elecsys, Roche) were evaluated in MBC patients (n=77) at the beginning of chemotherapy (pre-treatment value=A), after 20-30 days (first intermediate value=B), after 40-60 days (second intermediate value=C) and at the time the effectiveness of chemotherapy was evaluated with imaging (D). Response to treatment was assessed by standard WHO criteria criteria. For the assessment of biochemical progression and response, four criteria based on TMK were established. The first criterion of progression required that there was an increase ≥ 25% after 40-60 days (C) and the slope per day from B to C exceeds the slope from A to B. The second criterion of progression required that, at the time of staging, the value be ≥ 25% of the pre-treatment value (A), and also, increasing values from C until staging (D) were required. The first criterion of response required that the second intermediate value (C) be decreased by ≥ 25% compared to A (pre-treatment value) and C be lower than B (first intermediate value). The second criterion of response required that D be ≤ 25% of B and D be lower than C. Fifty-four (70%) patients showed a correlation between TMK and imaging results during chemotherapy. In 10 (13%) patients, no correlation was obtained, and in 13 (17%) patients, no biochemical statement was possible because of divergent TMK. In summary, after 1 month, no statement about treatment response was possible by using TMK. The effectiveness or ineffectiveness of treatment could be determined correctly in 40% of patients after 2 months and in 70% of patients after approximately 3 months. The data presented support the hypothesis that TMK are clinically relevant tools to monitor treatment response. Further improvements on their sensitivity can be probably achieved by a prospective study design and by combining with other biomarkers like CA-125 and HER2 shed antigen.