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B-lineage transcription factors and cooperating gene lesions required for leukemia development

Abstract

Differentiation of hematopoietic stem cells into B lymphocytes requires the concerted action of specific transcription factors, such as RUNX1, IKZF1, E2A, EBF1 and PAX5. As key determinants of normal B-cell development, B-lineage transcription factors are frequently deregulated in hematological malignancies, such as B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and affected by either chromosomal translocations, gene deletions or point mutations. However, genetic aberrations in this developmental pathway are generally insufficient to induce BCP-ALL, and often complemented by genetic defects in cytokine receptors and tyrosine kinases (IL-7Rα, CRLF2, JAK2 and c-ABL1), transcriptional cofactors (TBL1XR1, CBP and BTG1), as well as the regulatory pathways that mediate cell-cycle control (pRB and INK4A/B). Here we provide a detailed overview of the genetic pathways that interact with these B-lineage specification factors, and describe how mutations affecting these master regulators together with cooperating lesions drive leukemia development.

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Acknowledgements

We thank RP Kuiper, LT van der Meer and C Murre for critically reading the manuscript. ET, JH and BS are supported by grants from the Dutch childhood oncology foundation KiKa. FNvL is supported by a grant from The Quality of Life Gala foundation.

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Tijchon, E., Havinga, J., van Leeuwen, F. et al. B-lineage transcription factors and cooperating gene lesions required for leukemia development. Leukemia 27, 541–552 (2013). https://doi.org/10.1038/leu.2012.293

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