Written by | Zhao Bingqing, editor of | Zhou Yebin
Acute lymphoblastic leukemia (ALL) is the most common of all childhood cancers. With decades of advances in treatments, the overall cure rate for acute lymph in children can reach 90%. However, there are still some subtypes with poor prognosis, especially in infants who develop B cells before the age of one year, with a mortality rate of more than 50%. In infant b-cell rush, 70% to 80% of children carry a rearrangement of the KMT2A gene. Compared with children with only one gene rearrangement, children with KMT2A gene rearrangement had a significantly poor prognosis. 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 a study titled Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia in nature medicine magazine. The team analyzed the traditional transcriptome and the single-cell transcriptome and found that infant B cells carrying the KMT2A gene rearrangement were rushing, and a large number of cells were similar to the early precursor lymphocytes (ELPs) in the embryonic stage at the gene expression level, which may be the cause of the difficult treatment and poor prognosis of this gene mutation, and proposed a potential therapeutic target. This study is an important advance in high-risk infantile leukemia and offers implications for improving this refractory cancer in the future.
The researchers first analyzed traditional transcriptome data from more than 1,600 samples from St. Jude's Children's Hospital and the TARGET project. The samples covered a total of 28 subtypes of acute and non-lymphogenesis in children. By comparing each disease sample with a healthy bone marrow sample and performing deconvolution analysis, the most prominent cell type characteristics of each sample are obtained. Because childhood leukemia, especially infancy, is thought to have begun to develop in the fetal period, the researchers also listed a variety of fetal blood cells as a reference for comparison.
Traditional transcriptome data analysis yielded unexpected results, i.e., myeloid cell features were detected in acute non-gonorrhea samples, T cell features were detected in T cell rushes, and B cell features at multiple stages of differentiation were seen in B cell ALL. Most importantly, in a rapid lymphocyte (ELP) sample of infants carrying a rearrangement of the KMT2A gene, features of early precursor lymphocytes (ELPs) in the embryonic stage were seen. Among them, the sample carrying the KMT2A-AFF1 fusion gene has the strongest ELP cell signal, which is also the most common KMT2A gene rearrangement.
More than 1600 cases of acute and non-lymphatic cell characteristics in children at St. Jude Children's Hospital and the TARGET project
To confirm and further study the findings in the traditional transcriptome, the researchers conducted a single-cell transcriptome analysis of 6 infants with B-cell rapid lymphorrhea carrying a rearrangement of the KMT2A gene, including 1 sample of infant B-cell rapid lymph on day 8 of treatment (responding to treatment), 2 children on day 8 of treatment (no response to treatment), 3 relapse period samples, and 4 samples of infant b-cell rapid lymph with other types of genetic mutations as controls. Using a logistic regression-based cell control approach, the researchers directly compared each cell in a tumor sample with a human fetal bone marrow cell type to find the closest normal cell type.
The researchers found that infants with B-cell rush lymph, who carried the KMT2A gene rearrangement, had the most ELP-like cells in the initial sample, the recurrence sample, and the sample that did not respond to treatment. In the samples that responded well to treatment, there were almost no CELLS that resembled ELP. In children with mutations in other genes, non-ELP cells make up the majority.
In infant b cell rush, there are obvious differences in the main cell types of children carrying the KMT2A gene rearrangement (1 to 6) and children with other gene mutations (7 to 10).
The proportion and similarity of various cell types in infants with B-cell rapid lymphogenesis carrying different genetic variants
An important question is at what stage these ELP-like cells evolved. Researchers found a rare case in which a child carrying KMT2A was rearranged, with an initial onset of rapid lycology and then a few years later. In this case, the pediatric acute lymphatic sample had a large number of ELP signals, while the acute non-lymphatic sample did not. Whole genome sequencing of the acute, non-lymphatic, and remission phases showed that the child had developed genetic mutations at a very early stage of the embryo, and since then normal blood cells and cancer cells have developed separately. After the occurrence of KMT2A rearrangement, the two cancer cells developed separately into separate leukemia events. Thus, although they are the same patient, the acute and non-lymphatic samples differ in both genetic mutation profile and phenotype.
Timeline of genetic mutations in children with first-onset and non-lymphogenous onset
Next, to find possible therapeutic targets, the researchers took data from the traditional transcriptome and the single-cell transcriptome and directly compared the transcription of leukemia cells and ELPs. Using differential expression analysis, the researchers found genes that appeared differentially expressed in both comparisons, called the cancer core transcriptome.
The biggest difference between leukemia cells and normal ELPs is that they have both lymphocyte and myeloid characteristics. After further combination analysis, the researchers obtained several antigen combinations (SEMA4A+CD72, FLT3+CD72, LILRB1+CD72) expressed in most infant B cell rush cells carrying the KMT2A gene rearrangement. Combination-targeted drugs targeting these antigens will most likely advance the treatment of acute lymph in such infants.
Gene combinations and potential targets for rapid lymphatic representation of infant B cells carrying KMT2A gene rearrangements
In this paper, the researchers analyzed the traditional transcriptome and single-cell transcriptome of multiple types of leukemia to study the high-risk infant B-cell rush carrying the KMT2A gene rearrangement, compared healthy embryonic and childhood normal blood cells, and found that there are a large number of cells in this infant rapid lymphocyte that resemble the early precursor lymphocytes (ELPs) of the embryonic stage. The researchers further analyzed differential expression and extracted several sets of specific and representative gene combinations as potential therapeutic targets, which is expected to greatly improve the prognosis of this high-risk subtype in the future.
Writing
Editor-in-charge
make
Typography | Che Jie proofreads | uu