A three-gene signature and clinical outcome in pediatric acute myeloid leukemia

Objective. The aim of this research was to create a new genetic signature of immune checkpoint-associated genes as a prognostic method for pediatric acute myeloid leukemia (AML). Methods. Transcriptome profiles and clinical follow-up details were obtained in Therapeutically Applicable Research to Generate Effective Treatments (TARGET), a database of pediatric tumors. Secondary data was collected from the Gene Expression Omnibus (GEO) to test the observations. In univariate Cox regression and multivariate Cox regression studies, the expression of immune checkpoint-related genes was studied. A three-mRNA signature was developed for predicting pediatric AML patient survival. Furthermore, the GEO cohort was used to confirm the reliability. A bioinformatics method was utilized to identify the diagnostic and prognostic value. Results. A three-gene (STAT1, BATF, EML4) signature was developed to identify patients into two danger categories depending on their OS. A multivariate regression study showed that the immune checkpoint-related signature (STAT1, BATF, EML4) was an independent indicator of pediatric AML. By immune cell subtypes analyses, the signature was correlated with multiple subtypes of immune cells. Conclusion. In summary, our three-gene signature can be a useful tool to predict the OS in AML patients.

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Hyperleukocytosis predicts inferior clinical outcome in pediatric acute myeloid leukemia

Hematology ◽

10.1080/16078454.2020.1859169 ◽

2020 ◽

Vol 25 (1) ◽

pp. 507-514

Author(s):

Lu-Hong Xu ◽

Jing-Wen Wang ◽

Yin Wang ◽

Feng-Ying Yang

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Pediatric Acute Myeloid Leukemia ◽

Acute Myeloid

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Extensive mutational status of genes and clinical outcome in pediatric acute myeloid leukemia

Leukemia ◽

10.1038/leu.2009.172 ◽

2009 ◽

Vol 24 (1) ◽

pp. 205-209 ◽

Cited By ~ 5

Author(s):

H Lapillonne ◽

L Llopis ◽

A Auvrignon ◽

A Renneville ◽

M Labopin ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Clinical Outcome ◽

Myeloid Leukemia ◽

Pediatric Acute Myeloid Leukemia ◽

Mutational Status ◽

Acute Myeloid

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Measurable residual disease in pediatric acute myeloid leukemia: a systematic review

Expert Review of Anticancer Therapy ◽

10.1080/14737140.2021.1860763 ◽

2021 ◽

Vol 21 (4) ◽

pp. 451-459

Author(s):

W H Segerink ◽

V de Haas ◽

G J L Kaspers

Keyword(s):

Systematic Review ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Residual Disease ◽

Pediatric Acute Myeloid Leukemia ◽

Measurable Residual Disease ◽

Acute Myeloid

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A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

Cell Death and Disease ◽

10.1038/s41419-021-03738-0 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Matthew E. Massett ◽

Laura Monaghan ◽

Shaun Patterson ◽

Niamh Mannion ◽

Roderick P. Bunschoten ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Activity ◽

Leukemia Cell ◽

Gene Signature ◽

Pathological Feature ◽

Self Renewal ◽

Stem Cell Activity ◽

Molecular Mechanism Of Action ◽

Acute Myeloid

AbstractEpigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

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NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms22094575 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4575

Author(s):

Vincenza Barresi ◽

Virginia Di Bella ◽

Nellina Andriano ◽

Anna Provvidenza Privitera ◽

Paola Bonaccorso ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mutational Analysis ◽

Integrated Analysis ◽

Induction Phase ◽

Pediatric Acute Myeloid Leukemia ◽

Expression Arrays ◽

Primary Induction ◽

Induction Failure ◽

Acute Myeloid

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

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