Myeloid leukemia with transdifferentiation plasticity developing from T‐cell progenitors

Abstract

Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c-Myc expression, we show, at the single-cell level, that T-lymphoid progenitors retain broad malignant lineage potential with a high capacity to differentiate into myeloid leukemia. These T-cell-derived myeloid blasts retain expression of a defined set of T-cell transcription factors, creating a lymphoid epigenetic memory that confers growth and propagates myeloid/T-lymphoid plasticity. Based on these characteristics, we identified a correlating human leukemia cohort and revealed targeting of Jak2/Stat3 signaling as a therapeutic possibility. Collectively, our study suggests the thymus as a source for myeloid leukemia and proposes leukemic plasticity as a driving mechanism. Moreover, our results reveal a pathway-directed therapy option against thymus-derived myeloid leukemogenesis and propose a model in which dynamic progenitor differentiation states shape unique neoplastic identities and therapy responses.

T‐lymphoid progenitors – we know what they are, but know not what they may be

“…This is especially true for the poor‐risk disease of mixed‐phenotype acute leukemia (MPAL) (Matutes et al , ), which for many years suggested that early hematopoietic progenitors can have the potential to undergo either myeloid or lymphoid differentiation. In accordance, there have been numerous reports suggesting the persistence of a myeloid potential in early B‐ and T‐lymphoid precursors (Wada et al , ), and the current study by Riemke et al () showed that the expression of MYC/BCL2 in T‐lymphoid progenitors resulted not only in pure T cell but also in mixed myeloid/T‐cell phenotypes. Interestingly, unique features including a gene expression pattern similar to dendritic cells (DC) characterize the T‐lymphoid progenitor‐derived myeloid leukemia, which is in line with earlier findings showing preserved DC developmental potential during T‐lymphoid differentiation (Manz et al , ).…”

“…In line, putatively activating NOTCH1 mutations are found in several AML cases and gene expression signatures allow the detection of a respective “T‐cell origin” cohort. In the present study, published gene expression data sets suggest approximately 5% of all human AML cases to be of potential T‐cell progenitor origin, that is, showing hints for a pathogenesis similar to the murine MYC/BCL2‐driven model (Riemke et al , ).…”

“… An improved understanding of the biology underlying leukemogenesis, including the determination of the cells of leukemia origin, is of great importance as it can have immediate implications on patient treatment and management. The article by Riemke et al () provides further evidence that a subgroup of acute myeloid leukemia (AML), the most common acute leukemia in adults, might arise from T‐lymphoid progenitor cells. This study not only supports that the lymphoid fate of early T‐cell progenitors is not yet fully stabilized but also shows that under oncogenic conditions, this multilineage plasticity potential of T‐lymphoid progenitors can lead to transdifferentiation into myeloid leukemia.…”

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

“…The manufacture, quality control, storage, release and delivery of ATMPs The design and execution of early phase clinical trials with ATMPs The interdisciplinary management of toxicities The active follow-up of patients treated with ATMPs, Interact on both national and EU level Should be accredited in terms of process and structure quality by the local competent authority as the basis for a national accreditation May apply for the coverage of costs based on their national accreditation at health insurance companies for certain products Should be obliged to establish and maintain a network of exchange with other accredited centers to avoid redundancy and excessive consumption of resources and the potential to differentiate [29] may add to the general risks of defined cell populations and challenges the benefit of meticulous characterization of cellular components. Thus, detailed definition of a cellular product and subsequent correlation with clinical outcome will be an important step to further clarify these issues.…”

Uncovering a new cellular origin for acute myeloid leukemia with lineage plasticity

“…In a recently published study, 5 we addressed the question of the leukemic lineage fate outcome of oncogene-transformed Tcell precursors. Using CD4/CD8 double-negative (DN2) T-cell progenitors expressing either Myc/Bcl2 (v-myc avian myelocytomatosis viral oncogene homolog / B-cell CLL/lymphoma 2) or MLL-AF9 (mixed lineage leukemia-ALL1 fused gene from chromosome 9) oncogenes, we showed at the single cell level that transformed DN2 cells resulted not only in pure T-lymphoid leukemia as assumed but also in mixed myeloid/T-cell leukemia.…”