A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Zeng, Andy G.X.; Bansal, Suraj; Jin, Liqing; Mitchell, Amanda; Chen, Weihsu Claire; Abbas, Hussein A.; Chan-Seng-Yue, Michelle; Voisin, Véronique; Galen, Peter van; Tierens, Anne; Cheok, Meyling; Preudhomme, Claude; Dombret, Hervé; Daver, Naval; Futreal, Andrew; Minden, Mark D.; Kennedy, James A.; Wang, Jean; Dick, John E.

doi:10.1038/s41591-022-01819-x

Cited by 152 publications

(169 citation statements)

References 97 publications

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“…These genes were also highly expressed in some, but not all, of our diagnosis and relapse samples and also not consistentlty induced at relapse. Other studies based on larger numbers of unsorted cells [26] or deconvolution of bulk RNAsequencing [50] detected a hierarchy from primitive to differentiated AML tumor cells. They showed that the composition of tumor cells is patient-specific and associated with chemotherapy and drug sensitivity.…”

Section: Discussionmentioning

confidence: 95%

Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia

et al. 2022

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Background Acute myeloid leukemia (AML) is a heterogeneous and aggressive blood cancer that results from diverse genetic aberrations in the hematopoietic stem or progenitor cells (HSPCs) leading to the expansion of blasts in the hematopoietic system. The heterogeneity and evolution of cancer blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. In this study, we investigated the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs at genetic and transcriptional levels, and unveiled the underlying pathways and genes contributing to recurrence. Methods Whole-exome sequencing was used to detect somatic mutations and large copy number variations (CNVs). Single cell RNA-seq was performed to investigate the clonal heterogeneity between Dx-Re pairs and amongst patients. Results scRNA-seq analysis revealed extensive expression differences between patients and Dx-Re pairs, even for those with the same -presumed- initiating events. Transcriptional differences between and within patients are associated with clonal composition and evolution, with the most striking differences in patients that gained large-scale copy number variations at relapse. These differences appear to have significant molecular implications, exemplified by a DNMT3A/FLT3-ITD patient where the leukemia switched from an AP-1 regulated clone at Dx to a mTOR signaling driven clone at Re. The two distinct AML1-ETO pairs share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells evolved from the Dx cells. Conclusions In summary, the single cell RNA data underpinned the tumor heterogeneity not only amongst patient blasts with similar initiating mutations but also between each Dx-Re pair. Our results suggest alternatively and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.

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Section: Discussionmentioning

confidence: 95%

Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia

et al. 2022

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“…The strength of the block independently determined the overall degree of monocytic differentiation. Unlike cellular hierarchies identified from bulk data 40 , the availability of single cell resolution allowed us to distinguish stem cells from immature, "stem-like" progenitors, and pin-point a poor first-line chemotherapy response to the latter. This hypothesis goes in line with the kinetics of hematopoietic differentiation.…”

Section: Discussionmentioning

confidence: 99%

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

Beneyto-Calabuig

Ludwig

Kniffka

et al. 2022

Preprint

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Inter-patient variability and the similarity of healthy and leukemic stem cells have impeded the characterization of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. While residual healthy cells dominated the dormant stem cell compartment, active leukemic stem cells resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors were highly aberrant and constituted the disease-defining compartment: Their gene expression and differentiation state determined both chemotherapy response and the leukemia's ability to differentiate to transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers mis-regulated specifically in leukemic cells by intra-patient comparisons. Taken together, CloneTracer revealed a differentiation landscape that mimics its healthy counterpart and determines biology and therapy response in AML.

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“…BCL2 inhibitor venetoclax has shown promise in the clinical setting, although a majority of the initial responders relapse ( 38, 39 ). Beat AML analysis indicated that monocytic (Mono) AML cases associate with venetoclax resistance ( 40 ), as well KDM6A hi expressing male AMLs are relatively more tolerant to venetoclax (Figs. 5A-B).…”

Section: Resultsmentioning

confidence: 99%

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

Boila

Ghosh

Bandyopadhyay

et al. 2022

Preprint

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Acute myeloid leukemia (AML) is a heterogeneous, aggressive malignancy with dismal prognosis and with limited availability of targeted therapies. AML exhibits epigenetic deregulation and transcriptional plasticity that contributes to pathogenesis. KDM6 proteins are histone-3 lysine-27 demethylases that play major context dependent roles in AML evolution and therapy resistance. Here, we demonstrate that KDM6 demethylase function critically regulates DNA damage repair (DDR) gene expression programs in AML. Mechanistically, KDM6 family protein expression is regulated by genotoxic stress, with deficiency of KDM6A (UTX) and KDM6B (JMJD3) impairing DDR transcriptional activation and compromising repair potential. Acquired KDM6A loss-of-function mutations have been implicated in chemoresistance, although a significant percentage of relapsed AML have upregulated KDM6A. Based on these mechanistic findings, olaparib treatment significantly reduced engraftment of patient-derived xenografts. Thus KDM6A-mutant human primary AML samples have increased susceptibility to Poly-(ADP-ribose)-polymerase (PARP) inhibition in vivo. Crucially, a higher KDM6A expression is correlated with venetoclax tolerance. Loss of KDM6A increased mitochondrial activity, BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6A loss was accompanied with a downregulated BCL2A1, which is commonly associated with venetoclax resistance. Corroborating these results, dual targeting of PARP and BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing AML apoptosis, and primary AML cells carrying acquired KDM6A-domain mutations were even more sensitive to the combination. Together, our study illustrates a mechanistic rationale in support for a novel combination targeted therapy for human AML based on subtype heterogeneity, and establishes KDM6A as an important molecular regulator for determining therapeutic efficacy.

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A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia

Cited by 152 publications

References 97 publications

Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia

Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia

KDM6A loss sensitizes human acute myeloid leukemia to PARP and BCL2 inhibition

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