Understanding the biology of childhood cancers provides essential information for improving therapeutic strategies and outcomes for children living with these diseases. Acute myeloid leukemia (AML) is one such cancer that occurs in children and is associated with a high mortality risk. Infant AML – classified as AML in children under three years old - while rare, is a heterogenous disease state, subtypes of which are not well characterized. A recent study led by Dr Hamid Bolouri member at the Benaroya Research Institute and Affiliate Investigator in the Human Biology Division at Fred Hutch, and members of Dr Soheil Meshinchi’s Laboratory, including Rhonda Ries, in Fred Hutch’s Clinical Research Division, sought to better understand infant AML. Their work, recently published in PLOS ONE, concentrated on multiple sequencing approaches to define the multiomic landscape of infant AML. Their research revealed that infant AML activates a distinct B-cell specific gene network which is not present in older children diagnosed with AML. Excitingly, the authors further described the presence of multiple upregulated genes including BRD4 for which clinical therapies already exist.
The authors accessed over 1000 diagnostic samples from infants with AML and children over 5 years old with AML. They undertook large-scale genomic analysis efforts including bulk RNA-sequencing, microRNA-sequencing, and DNA methylation profiling to compare the two AML cohorts. Interestingly, they observed age-specific gene expression differences between the two AML populations. A 56 gene signature, the majority of which is linked to B-cell development, is strongly associated with infant AML. Investigating further, they determined a distinct overlap in expression patterns between infant AML and B-ALL (acute lymphocytic leukemia), a different form of acute leukemia. This finding suggested an infant AML specific gene expression profile, one that is not present in AML in children and young adults. “This work continues to build upon earlier observations from our lab – we have shown, not only that pediatric AML is very different from adult AML but also that infant AML (less than 3 years of age) has an even more distinct profile than other childhood age groups,” noted Ries.
Continuing this age-related trend, the authors observed an upregulation of microRNAs in infant AML but not in AML in older children, among them microRNAs mir-150 and mir-151. Interestingly, they observed down-regulation of Let7 microRNAs which corresponded with high expression of LIN28B, a known repressor of Let7. This increased expression of LIN28B, in addition to IGFBP, was exclusively present in infant AML. Examining this further, the authors detailed how BRD4 an epigenetic regulator of LIN28B is also upregulated in infant AML. Next, DNA methylation analysis confirmed that BRD4 and its targets are demethylated in infant AML. To validate these encouraging results, they undertook quantitative PCR of a subset of upregulated genes subsequently confirming their findings of an expression network specific to infant AML.
The authors highlighted the potential for clinical therapies that already exist to target genes upregulated in infant AML, for example BRD4 can be targeted by bromodomain inhibitors. Further, the overlap in gene expression patterns with B-ALL is a key finding, as patients with B-ALL respond well to some immunotherapies such as CAR-T therapy which could also potentially be utilized in infant AML. “Biological similarities of infant AML to that of ALL raises the question whether these infants that are at high risk of relapse with conventional therapies may benefit from ALL based therapies,” explained Dr Meshinchi. Discussing their overall results, Dr Bolouri stated “Our findings highlight the modular manner in which the immune system regulates the development and differentiation of immune cells in the bone marrow. We show that these regulatory modules can be inappropriately activated in AML, resulting in the poorer outcomes associated with infant AML.” “This work demonstrates that despite morphological similarities, infants with AML have a distinct transcriptome profile that appears to have similarities to that of ALL,” added Dr Meshinchi.
This important research would not have been achievable without generous support from patients living with AML and their families. As Dr Bolouri emphasized “studies like this are made possible by the large-scale cohorts and multi-modal genome-wide data sets empowered firstly by the children and families who donated samples, and secondly through the support of multiple agencies.” Elaborating further, Ries explained how “having access to samples collected from large clinical trials through cooperative groups, like the Children’s Oncology Group, has resulted in us building the largest database of childhood AML samples worldwide. This is extremely important for a rare cancer, which itself contains many rare subtypes. Only through the collection and analysis of over 2,000 tumor samples can we make observations and correlations to clinical outcome.”
This work was supported by funding from the National Cancer Institute, National Institute of Health, Target Pediatric AML, Children’s Oncology Group Foundation, The Rally Foundation for Childhood Cancer Research and The Jeffrey Pride Foundation for Pediatric Cancer Research.
UW/Fred Hutch Cancer Consortium member Soheil Meshinchi contributed to this work.
Bolouri H, Ries R, Pardo L, Hylkema T, Zhou W, Smith JL, Leonti A, Loken M, Farrar JE, Triche TJ Jr, Meshinchi S. A B-cell developmental gene regulatory network is activated in infant AML. PLoS One. 2021 Nov 18;16(11):e0259197. doi: 10.1371/journal.pone.0259197. PMID: 34793513; PMCID: PMC8601427.