Writing | Bingqing Zhao Editor | Yebin Zhou
Acute lymphoblastic leukemia (ALL) is the most common of all childhood cancers. With advances in treatment over the decades, the overall cure rate for acute lymphoblastic infection in children can reach 90%. However, there are still some subtypes with poor prognosis, especially infants with acute B-cell lymphoma with onset before the age of one year, the mortality rate exceeds 50%. In infants with B-cell acute lymphoma, 70% to 80% of infants carry KMT2A gene rearrangements. Children with KMT2A gene rearrangement had a significantly poorer prognosis than those with only another gene rearrangement. As a histone methyltransferase, KMT2A plays an important role in both gene expression regulation and cell differentiation.
On March 14, 2022, three teams from the UK published online in the journal Nature Medicine entitled Single-cell transcriptomics reveals a distinct developmental A study of state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia. The team analyzed the traditional transcriptome and single-cell transcriptome, and found that infant B cells with KMT2A gene rearrangement had a large number of cells similar to early embryonic precursor lymphocytes (ELP) in gene expression level, which may be The reasons for the difficulty in treatment and poor prognosis of such gene mutations, and potential therapeutic targets are proposed. This study is an important advance in high-risk infantile leukemia and provides implications for future improvements in this difficult-to-treat cancer.
The researchers first analyzed traditional transcriptome data from more than 1,600 samples from St. Jude Children’s Hospital and the TARGET project. These samples covered a total of 28 subtypes of acute and non-diabetic childhood leprosy. The most prominent cell type signatures for each sample were obtained by comparing and deconvolutional analysis of each diseased and healthy bone marrow sample. Because childhood leukemia, especially infancy leukemia, is thought to have begun to develop in the fetus, the researchers also included a variety of fetal blood cells for comparison.
Traditional transcriptomic data analysis yielded the expected results, with myeloid signatures detected in acute lymphoblastic samples and T cell signatures detected in T cell acute lymphomas, B-cell signatures at multiple stages of differentiation are seen in B-cell ALL. Most importantly, early embryonic precursor lymphocytes (ELP) features were seen in infant B-cell acute lymphoid samples harboring KMT2A gene rearrangements. Among them, the samples carrying the KMT2A-AFF1 fusion gene had the strongest ELP cell signal, which is also the most common KMT2A gene rearrangement.
Cell characteristics of more than 1,600 children with acute lymphoblastic lymphoma and acute lymphoblastic lymphoma from St. Jude Children’s Hospital and the TARGET project
To confirm and further study the traditional transcriptome findings, the researchers performed single-cell transcriptome analysis of 6 infants with KMT2A gene rearrangement in infants with B-cell acute lymphoma , and included samples from patient 1 on the 8th day of treatment (responding to treatment), patient 2 on the 8th day of treatment (non-responder to treatment), and the samples of patient 3 in the relapse period, and 4 patients carried other types of gene mutations samples from infants with acute lymphoblastic B-cell lymphoma served as controls. Using a logistic regression-based approach to cell comparisons, the researchers directly compared each cell in a tumor sample to a human fetal bone marrow cell type, looking for its closest normal counterpart.
The researchers found that infants with KMT2A gene rearrangements with B-cell acute lymphoma had the highest number of ELP-like cells in newly diagnosed samples, relapsed samples, and samples that did not respond to treatment. There were few ELP-like cells in the samples that responded well to the treatment. In children with other genetic mutations, non-ELP cells predominate.
In infants with acute B-cell lymphoma, the main cell types of children with KMT2A gene rearrangement (1-6) and those with other gene mutations (7-10) are significantly different
Proportion and similarity of various cell types in infants with B-cell acute lymphoma with different gene variants
An important question is at what stage these ELP-like cells evolved. ResearchThe staff found a rare case, a child with KMT2A rearrangement, who initially developed acute lymphadenopathy and developed acute non-leukemia several years later. In this case, the acute lymphoblastic sample from the child had a large number of ELP signals, but the acute nonlymphatic sample did not. Whole-genome sequencing of the acute lymphocytic, acute non-lymphatic and remission stages showed that the child had a genetic mutation in the very early embryo, and since then normal blood cells and cancer cells have developed independently. After the KMT2A rearrangement occurred, the two cancer cells developed separately into independent leukemia events. Therefore, although it is the same patient, the acute lymphoblastic and acute non-leukemia samples differ in gene mutation spectrum and phenotype.
Gene mutation timeline in children with first-onset acute lymphoma and later onset of acute non-leukemia
Next, in order to find possible therapeutic targets, the researchers took data from the traditional transcriptome and single-cell transcriptome to directly compare the transcriptional profiles of leukemia cells and ELPs. Through differential expression analysis, the researchers found genes that were differentially expressed in both comparisons, called the cancer core transcriptome.
Leukemia cells differ from normal ELP in that they have both lymphocyte and myeloid features. After further combinatorial analysis, the researchers obtained several antigen combinations (SEMA4A+CD72, FLT3+CD72, LILRB1+CD72), which were expressed in most infant B-cell acute lymphocytes carrying KMT2A gene rearrangement. Combination-targeted drugs targeting these antigens will likely advance the treatment of such infantile acute lymphoblastic infections.
Representative gene combinations and potential targets of infant B cells with KMT2A gene rearrangement in acute lymphoblastic lymphoma
In this article, researchers analyzed the traditional and single-cell transcriptomes of multiple leukemia types for the study of high-risk infant B-cell acute lymphoma harboring KMT2A gene rearrangements, comparing In healthy embryonic and childhood normal blood cells, a large number of cells in this infantile acute lymphoid were found to resemble embryonic early precursor lymphocytes (ELP). The researchers further extracted several sets of specific and representative gene combinations through differential expression analysis, which are potential therapeutic targets, which are expected to greatly improve the prognosis of this high-risk subtype in the future.
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