SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells

Oncogene
M SprangersM Müschen

Abstract

Perpetual V(D)J recombinase activity involving multiple DNA double-strand break events in B-cell lineage leukemia and lymphoma cells may introduce secondary genetic aberrations leading towards malignant progression. Here, we investigated defective negative feedback signaling through the (pre-) B-cell receptor as a possible reason for deregulated V(D)J recombinase activity in B-cell malignancy. On studying 28 cases of pre-B-lymphoblastic leukemia and 27 B-cell lymphomas, expression of the (pre-) B-cell receptor-related linker molecule SLP65 (SH2 domain-containing lymphocyte protein of 65 kDa) was found to be defective in seven and five cases, respectively. SLP65 deficiency correlates with RAG1/2 expression and unremitting V(H) gene rearrangement activity. Reconstitution of SLP65 expression in SLP65-deficient leukemia and lymphoma cells results in downregulation of RAG1/2 expression and prevents both de novo V(H)-DJ(H) rearrangements and secondary V(H) replacement. We conclude that iterative V(H) gene rearrangement represents a frequent feature in B-lymphoid malignancy, which can be attributed to SLP65 deficiency in many cases.

References

Mar 6, 1998·Oncogene·M A YuilleD Catovsky
Mar 10, 2001·Nature Genetics·K K Khanna, S P Jackson
Nov 1, 2001·Cell Death and Differentiation·K K KhannaT D Mulhern
Jul 23, 2003·Immunity·Zhixin ZhangMax D Cooper
Dec 22, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Florian KleinMarkus Müschen
Jun 9, 2005·The Journal of Experimental Medicine·Niklas FeldhahnMarkus Müschen

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Citations

Dec 3, 2008·Blood·Joji NakayamaDaisuke Kitamura
Mar 4, 2014·The Journal of Allergy and Clinical Immunology·Chantal Lagresle-PeyrouClaudine Schiff
Jun 22, 2018·Omics : a Journal of Integrative Biology·Tania IslamNurul Haque Mollah
Jan 6, 2018·Nature Reviews. Cancer·Markus Müschen

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