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Biologic characteristics of B-lymphoblastic leukemia correspond to immunoglobulin gene diversity

ABSTRACT: Biologic characteristics of B-lymphoblastic leukemia correspond to immunoglobulin gene diversity

PROVIDER: PRJNA828588 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18702000_1.fastq.gz	Fastqsanger.gz
	SRR18702000_2.fastq.gz	Fastqsanger.gz
	SRR18702001_1.fastq.gz	Fastqsanger.gz
	SRR18702001_2.fastq.gz	Fastqsanger.gz
	SRR18702002_1.fastq.gz	Fastqsanger.gz

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Biologic characteristics of B-lymphoblastic leukemia correspond to immunoglobulin gene diversity [array]

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Biologic characteristics of B-lymphoblastic leukemia correspond to immunoglobulin gene diversity [sequencing]

Project description:It remains unclear whether the variable biologic features of B-lymphoblastic leukemia (B-ALL) reflect distinct cells of origin in the hierarchy of early B cell development. Recombination activating genes (RAG) 1 and 2 rearrange the immunoglobulin heavy chain (IgH) locus in B lymphoid progenitors, resulting in unique variable (Vh), diversity (D), and joining (Jh) gene rearrangements. To test whether discrete properties of each B-ALL reflect derivation from distinct developmental B cell stages, we assessed the relationship between IgH variable gene (IGHV) characteristics and gene expression. Using targeted, pre-treatment IgH sequencing of 22 patients’ B-ALL, we discovered 2 distinct groups: leukemias with RAG-mediated intra-clonal IGHV sequence diversification (‘diverse’; N=9, 40.9%) and those lacking diversity (‘homogeneous’; N=10, 45.5%). Three patients (13.6%) lacked a dominant IgH sequence. In the ‘diverse’ cohort, we observed extensive subclone evolution arising from Vh gene recombination after neoplastic transformation (median: 482 subclones; range 2-2600). In the ‘homogeneous’ cohort, all IgH clones lacked subclone evolution. The ‘diverse’ cohort demonstrated enriched expression of genes associated with regulation of a hematopoietic stem cell state, while ‘homogeneous’ cases showed enriched expression of genes involving cell fate commitment. Furthermore, distinct IgH clonotypes within a single patient could be individually diverse or homogenous. Single cell analysis indicated that within a single patient, only occasional IgH clonotypes were expressed; IGHV-expressing leukemia cells were characterized by distinctive phenotypes including RAG1 pathway up-expression. In summary, pre-treatment IgH composition reflects the B cell stage at leukemic initiation and provides insights about the biologic mechanisms of genetic diversity in B-ALL.

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Biologic characteristics of B-lymphoblastic leukemia correspond to immunoglobulin gene diversity

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Biologic characteristics of B-lymphoblastic leukemia correspond to immunoglobulin gene diversity [array]

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