Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia
Menée à l'aide d'échantillons de sang et de moelle osseuse ainsi que d'une technique de séquençage de l'ARN à l'échelle d'une seule cellule, cette étude met en évidence, pour les cellules de leucémie aiguë lymphoblastique infantile avec réarrangement du gène KMT2A, un phénotype transcriptionnel plus proche de celui des cellules foetales précurseurs des lymphocytes que de celui des cellules des autres types de leucémie aiguë lymphoblastique
Résumé en anglais
KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid–lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.
