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570 Pre-BCR Surrogate Light Chain Components VPREB1 and IGLL1 Function As Pre-BCR-Independent Tumor Suppressors in Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: ALL Taxonomy, Pathway Activation and Signaling
Hematology Disease Topics & Pathways:
ALL, Leukemia, Diseases, Lymphoid Malignancies
Monday, December 3, 2018: 8:15 AM
Room 25B (San Diego Convention Center)

Kadriye Nehir Cosgun, PhD1*, Rudi W Hendriks, PhD2*, Ross A Dickins, PhD3*, Nora Heisterkamp, PhD1* and Markus Muschen, MD1,4,5

1Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA
2Department of Immunology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands
3Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
4Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia CA, Monrovia, CA
5Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia CA, San Francisco, CA

Background: IGLL1 and VPREB1 encode for the l5 and VpreB components, respectively, of the surrogate light chain (SLC) of the pre-B cell receptor (pre-BCR). During early B-cell development, immunoglobulin (Ig) heavy chains pairs with SLCs to form the pre-BCR, a central signaling unit that drives proliferation and survival. Accordingly, germline mutations of IGLL1 (Minegishi J Exp Med 1998) and VPREB1 (Conley Immunol Rev 2005) are associated with profound B-cell defects and agammaglobulinemia in humans. However, somatic deletions of VPREB1 gene are frequent lesions in B-ALL and occur in >10% of B-ALL cases (Mangum et al., Leukemia 2014; Geng et al., Cancer Cell 2015), the significance of which is not clear. Since VPREB1 deletions are typically present at the time of diagnosis and are rarely acquired as secondary lesions at the time of relapse (Kuster Blood 2011), we hypothesized that loss of VPREB1 represents an early and essential event in leukemogenesis.

Experimental Approach and Results: For genetic gain and loss of function analysis of VPREB1 and IGLL1, we established leukemia models based on pre-B cells from Igll1-/- mice (Kitamura Cell 1992), and Vpreb1-Igll1 double-transgenic mice (Van Loo Immunity 2007). Loss of Igll1 completely abrogated SLC expression on the surface of pre-B cells. In contrast, VpreB1-Igll1 double-transgenic pre-B cells expressed constitutively higher surface levels of SLC as part of their pre-BCR as evidenced by flow cytometry. Compared to wildtype controls, Igll1-/- pre-B cells lacking the ability to express a functional SLCs were more readily transformed by BCR-ABL1 oncogene. However, pre-B cells of VpreB1-Igll1 transgenic mice, were not permissive to BCR-ABL1 mediated transformation.

In agreement with these results, VpreB1-Igll1 double-transgenic pre-B cells were resistant transformation by BCR-ABL1 in vivo. BCR-ABL1-transgenic mice with enforced expression Vpreb1-Igll1 remained disease-free for more than nine months, whereas the vast majority of BCR-ABL1-transgenic mice downregulated pre-BCR surface expression and developed lethal B-ALL within 90 days of birth (n=34, P<0.0001). Compared to wildtype pre-B cells, double-transgenic expression of VpreB-Igll1 interfered with oncogenic BCR-ABL1 tyrosine kinase signaling and suppressed phosphorylation of Btk, Syk and Src kinases resulting in cell cycle arrest and reduced colony formation ability. To test whether SLC tumor suppressive function depends on pre-BCR activity, we studied BCR-ABL1-mediated transformation of VpreB1-Igll1 double-transgenic pre-B cells on a Rag1-deficient background. Rag1-/- pro-B cells lack the ability to rearrange Ig V, D and J-gene segments and cannot express a functional Ig mHC, the central structural element of the pre-BCR. Surprisingly, Rag1-/- VpreB1-Igll1 double-transgenic pro-B cells were also resistant to BCR-ABL1-mediated transformation. These findings provide genetic evidence that Vpreb1 and Igll1 exert tumor suppressive effect on B cells regardless of functional pre-BCR expression.

Conclusion: The VpreB and Igll1 surrogate light chain components of the pre-BCR act as a tumor suppressors in pre-B ALL cells. Interestingly, the tumor suppressor function of both VpreB and Igll1 is independent from their SLC-role in pre-BCR signaling: Vpreb1- and Iggl1-mediated tumor suppression was effective, regardless of pre-BCR function. These findings provide genetic evidence that VpreB and Igll1 have pre-BCR- and SLC-independent functions that prevent malignant transformation and limit proliferation of normal pre-B cells. Our findings support the hypothesis that VPREB1 deletion represents an early event during clonal evolution towards pre-B ALL, facilitating subsequent steps of leukemic transformation.

Disclosures: No relevant conflicts of interest to declare.

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