scholarly journals Single cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia

2021 ◽  
Author(s):  
Gulay B. Ulukaya ◽  
Beena E. Thomas ◽  
Swati S. Bhasin ◽  
Hope Mumme ◽  
Bhakti Dwivedi ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Acid Oxidation ◽  
P Value ◽  
Pediatric Acute Myeloid Leukemia ◽  
Tumor Microenvironments ◽  
Acute Myeloid

Abstract Relapse- and continuous complete remission (CCR)-associated pediatric acute myeloid leukemia (AML) patient bone marrows collected at the time of diagnosis (Dx), end of induction (EOI) and relapse were analyzed by single cell RNA sequencing. A novel AML blasts-associated 7-genes signature (CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH) displayed a strong correlation with blast percentages and overall survival in the TARGET AML dataset (HR = 2.3; P-value = .007). Distinct clusters of AML-blasts at Dx were observed for relapse- and CCR-associated samples with differential expression of genes associated with survival. Relapse-associated samples demonstrated enrichment of exhausted T cells and M2 macrophages as opposed to inflammatory M1 macrophages in CCR-associated samples at Dx. EOI treatment resistant blast cells overexpressed fatty acid oxidation, tumor growth and stemness genes. Also, a relapse-associated EOI samples T cells subset showed downregulation of MHC Class I and regulatory genes. Altogether, this study deeply characterizes pediatric AML relapse-/CCR-associated tumor microenvironment transcriptome landscape.

scholarly journals Single cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia

2021 ◽  
Author(s):  
Gulay Ulukaya ◽  
Beena Thomas ◽  
Swati Bhasin ◽  
Hope Mumme ◽  
Bhakti Dwivedi ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Acid Oxidation ◽  
P Value ◽  
Pediatric Acute Myeloid Leukemia ◽  
Tumor Microenvironments ◽  
Acute Myeloid

Abstract Relapse- and continuous complete remission (CCR)-associated pediatric acute myeloid leukemia (AML) patient bone marrows collected at the time of diagnosis (Dx), end of induction (EOI) and relapse were analyzed by single cell RNA sequencing. A novel AML blasts-associated 7-genes signature (CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH) displayed a strong correlation with blast percentages and overall survival in the TARGET AML dataset (HR=2.3; P-value=.007). Distinct clusters of AML-blasts at Dx were observed for relapse- and CCR-associated samples with differential expression of genes associated with survival. Relapse-associated samples demonstrated enrichment of exhausted T cells and M2 macrophages as opposed to inflammatory M1 macrophages in CCR-associated samples at Dx. EOI treatment resistant blast cells overexpressed fatty acid oxidation, tumor growth and stemness genes. Also, a relapse-associated EOI samples T cells subset showed downregulation of MHC Class I and regulatory genes. Altogether, this study deeply characterizes pediatric AML relapse-/CCR-associated tumor microenvironment transcriptome landscape.

scholarly journals Massively parallel quantification of phenotypic heterogeneity in single cell drug responses

2020 ◽  
Author(s):  
Benjamin B. Yellen ◽  
Jon S. Zawistowski ◽  
Eric A. Czech ◽  
Caleb I. Sanford ◽  
Elliott D. SoRelle ◽  
...  
Keyword(s):  
Machine Learning ◽  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Phenotypic Heterogeneity ◽  
Massively Parallel ◽  
Cell Analysis ◽  
On Chip ◽  
Acute Myeloid

AbstractSingle cell analysis tools have made significant advances in characterizing genomic heterogeneity, however tools for measuring phenotypic heterogeneity have lagged due to the increased difficulty of handling live biology. Here, we report a single cell phenotyping tool capable of measuring image-based clonal properties at scales approaching 100,000 clones per experiment. These advances are achieved by exploiting a novel flow regime in ladder microfluidic networks that, under appropriate conditions, yield a mathematically perfect cell trap. Machine learning and computer vision tools are used to control the imaging hardware and analyze the cellular phenotypic parameters within these images. Using this platform, we quantified the responses of tens of thousands of single cell-derived acute myeloid leukemia (AML) clones to targeted therapy, identifying rare resistance and morphological phenotypes at frequencies down to 0.05%. This approach can be extended to higher-level cellular architectures such as cell pairs and organoids and on-chip live-cell fluorescence assays.

scholarly journals Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kiyomi Morita ◽  
Feng Wang ◽  
Katharina Jahn ◽  
Tianyuan Hu ◽  
Tomoyuki Tanaka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Clonal Evolution ◽  
Evolutionary Process ◽  
Treatment Resistance ◽  
Clonal Diversity ◽  
Clonal Architecture ◽  
Acute Myeloid

AbstractClonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.

scholarly journals Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Meghali Goswami ◽  
Gege Gui ◽  
Laura W. Dillon ◽  
Katherine E. Lindblad ◽  
Julie Thompson ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Immune Checkpoint Blockade ◽  
Effector Memory ◽  
Open Label ◽  
Immunological Changes ◽  
Acute Myeloid

The powerful graft versus leukemia effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable pre-clinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease. We report here the results of 17-H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label ten-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML). In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using TCRb; sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable anti-leukemic response during treatment. Addition of pembrolizumab to ten-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

scholarly journals Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia

2022 ◽  
Vol 10 (1) ◽  
pp. e003392
Author(s):  
Meghali Goswami ◽  
Gege Gui ◽  
Laura W Dillon ◽  
Katherine E Lindblad ◽  
Julie Thompson ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Effector Memory ◽  
Open Label ◽  
Immunological Changes ◽  
Acute Myeloid

BackgroundThe powerful ‘graft versus leukemia’ effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease.MethodsWe report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).ResultsIn this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment.ConclusionAddition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.

scholarly journals Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis

Blood ◽  
2017 ◽  
Vol 130 (1) ◽  
pp. 48-58 ◽  
Author(s):  
Catherine C. Smith ◽  
Amy Paguirigan ◽  
Grace R. Jeschke ◽  
Kimberly C. Lin ◽  
Evan Massi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Single Cell Analysis ◽  
Cell Analysis ◽  
Mechanisms Of Resistance ◽  
Key Points ◽  
Acute Myeloid

Key Points Polyclonal mechanisms of resistance, demonstrated by single-cell analysis, occur in the majority of AML patients who relapse on quizartinib.

Single-cell whole exome and targeted sequencing in NPM1/FLT3 positive pediatric acute myeloid leukemia

2017 ◽  
Vol 65 (2) ◽  
pp. e26848 ◽  
Author(s):  
Christiane Walter ◽  
Christian Pozzorini ◽  
Katarina Reinhardt ◽  
Robert Geffers ◽  
Zhenyu Xu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Targeted Sequencing ◽  
Pediatric Acute Myeloid Leukemia ◽  
Whole Exome ◽  
Acute Myeloid
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