Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

Abstract

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

Acquired immune resistance is associated with interferon signature and modulation of KLF6/c‐MYB transcription factors in myeloid leukemia

“…Therefore, the antitumor immune reactions modelled as MLLRs had a prompt and significant impact on the leukemia blasts enabling alternative cellular programs for retaining viability and weakening immunogenicity which may persist for variable periods in the residual populations. Duration of the resistance is dependent on the continuum of selection pressure whereas cessation of the therapy can result in reacquisition of the proliferative state by AML cells [20, 21]. In our study, THP‐1 was the most affected cell line from the MLLRs.…”

“…Accordingly, the myeloid leukemia cells have been recognized with elaborate immune escape properties and display high adaptation capacities to cope with antitumor immunity [8,[27][28][29]. The interplay between the genetic and immune landscapes of AML leads to considerable heterogeneity which increases the possibility of blast populations emerging with resistance to therapeutics and thriving under unfavorable conditions [20,21,30]. The selection and adaptation of leukemia cells are dynamic processes, which continue during therapies such as the allogenic bone marrow transplantation and the GvL responses and facilitate disease progression and relapse [6,14,29].…”

“…The differences in gene expression signatures, maturation state, and plasticity have emerged as the major sources of relapse or resistance in AML [20,21]. The immune responses may create a dynamic and unstable microenvironment that drives the leukemic blasts to modify their biological program and adapt to novel conditions.…”

“…Immune resistance might be transiently acquired in response to immune reactions [20,21]; therefore, the ieAML cells were established in long-term cultures, and their viability, proliferation, and immunomodulatory capacities were assessed. The viability of the ieAML cells was sustained upon continuous culturing (nonapoptotic cells >85%) (Fig.…”