Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia

Hubmann, Rainer; Hilgarth, Martin; Löwenstern, Tamara; Lienhard, Andrea; Sima, Filip; Reisinger, Manuel; Hobel-Kleisch, Claudia; Porpaczy, Edit; Haferlach, Torsten; Hoermann, Gregor; Laccone, Franco; Jungbauer, Christof; Valent, Peter; Staber, Philipp B.; Shehata, Medhat; Jäger, Ulrich

doi:10.3390/ijms252312581

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Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia

by

Rainer Hubmann

^1,2,3,*,

Martin Hilgarth

¹,

Tamara Löwenstern

⁴

,

Andrea Lienhard

³,

Filip Sima

³,

Manuel Reisinger

³,

Claudia Hobel-Kleisch

³,

Edit Porpaczy

¹

,

Torsten Haferlach

⁵,

Gregor Hoermann

^5,6

,

Franco Laccone

⁴

,

Christof Jungbauer

³,

Peter Valent

^1,2,6

,

Philipp B. Staber

^1,2,6,

Medhat Shehata

^1,2,† and

Ulrich Jäger

^1,2,6,†

¹

Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria

²

Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria

³

Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, 1040 Vienna, Austria

⁴

Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria

⁵

MLL Munich Leukemia Laboratory, 81377 Munich, Germany

⁶

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria

^*

Author to whom correspondence should be addressed.

^†

These authors shared the senior authorship.

Int. J. Mol. Sci. 2024, 25(23), 12581; https://doi.org/10.3390/ijms252312581

Submission received: 31 October 2024 / Revised: 15 November 2024 / Accepted: 20 November 2024 / Published: 22 November 2024

(This article belongs to the Special Issue Notch Signaling Pathways)

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Abstract

Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common NOTCH2ΔNRR-DEL2 deletion is associated with two intronic single nucleotide variations (SNVs) which either create (CTTAT, G>A for rs2453058) or destroy (CTCGT, A>G for rs5025718) a putative splicing branch point sequence (BPS). Phylogenetic analysis demonstrates that rs2453058 is part of an ancient NOTCH2 gene variant (*1A01) which is associated with type 2 diabetes mellitus (T2DM) and is two times more frequent in Europeans than in East Asians, resembling the differences in CLL incidence. In contrast, rs5025718 belongs to a recent NOTCH2 variant (*1a4) that dominates the world outside Africa. Nanopore sequencing indicates that somatic reciprocal crossing over between rs2453058 (*1A01) and rs5025718 (*1a4) leads to recombined NOTCH2 alleles with altered BPS patterns in NOTCH2*1A01/*1a4 CLL cases. This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited NOTCH2 variants might be relevant to CLL etiology and may at least partly explain its geographical clustering.

Keywords: NOTCH2; gain of function; haplotypes; somatic recombination; evolution; CLL

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MDPI and ACS Style

Hubmann, R.; Hilgarth, M.; Löwenstern, T.; Lienhard, A.; Sima, F.; Reisinger, M.; Hobel-Kleisch, C.; Porpaczy, E.; Haferlach, T.; Hoermann, G.; et al. Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia. Int. J. Mol. Sci. 2024, 25, 12581. https://doi.org/10.3390/ijms252312581

AMA Style

Hubmann R, Hilgarth M, Löwenstern T, Lienhard A, Sima F, Reisinger M, Hobel-Kleisch C, Porpaczy E, Haferlach T, Hoermann G, et al. Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia. International Journal of Molecular Sciences. 2024; 25(23):12581. https://doi.org/10.3390/ijms252312581

Chicago/Turabian Style

Hubmann, Rainer, Martin Hilgarth, Tamara Löwenstern, Andrea Lienhard, Filip Sima, Manuel Reisinger, Claudia Hobel-Kleisch, Edit Porpaczy, Torsten Haferlach, Gregor Hoermann, and et al. 2024. "Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia" International Journal of Molecular Sciences 25, no. 23: 12581. https://doi.org/10.3390/ijms252312581

APA Style

Hubmann, R., Hilgarth, M., Löwenstern, T., Lienhard, A., Sima, F., Reisinger, M., Hobel-Kleisch, C., Porpaczy, E., Haferlach, T., Hoermann, G., Laccone, F., Jungbauer, C., Valent, P., Staber, P. B., Shehata, M., & Jäger, U. (2024). Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia. International Journal of Molecular Sciences, 25(23), 12581. https://doi.org/10.3390/ijms252312581

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Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia

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