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Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region.

Gostissa M, Yan CT, Bianco JM, Cogné M, Pinaud E, Alt FW - Nature (2009)

Bottom Line: Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations.We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations.As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

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Deletion of the IgH3’RR abrogates development of peripheral B cell lymphomasa. Left: Kaplan-Meier curve of the CXPR+/- (n=22) and CXPR-/- (n=17) cohorts. Curves represent total survival. Right: Percentage of mice in the CXPR+/- and CXPR-/- cohorts succumbing to B cell lymphomas, thymic lymphomas or to other cause of death. b. Southern blot analysis of CXPR+/- tumor DNA with probes indicated on the right of each panel. Numbers refer to individual mice in the cohort (see Supp. Table 2). K, kidney, used as control; Tu, tumor. A schematic of the c-myc locus, indicating the 5’ and 3’ probes used to detect c-myc rearrangements is on the top.
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Figure 2: Deletion of the IgH3’RR abrogates development of peripheral B cell lymphomasa. Left: Kaplan-Meier curve of the CXPR+/- (n=22) and CXPR-/- (n=17) cohorts. Curves represent total survival. Right: Percentage of mice in the CXPR+/- and CXPR-/- cohorts succumbing to B cell lymphomas, thymic lymphomas or to other cause of death. b. Southern blot analysis of CXPR+/- tumor DNA with probes indicated on the right of each panel. Numbers refer to individual mice in the cohort (see Supp. Table 2). K, kidney, used as control; Tu, tumor. A schematic of the c-myc locus, indicating the 5’ and 3’ probes used to detect c-myc rearrangements is on the top.

Mentions: Specific inactivation of Xrcc4 by a loxP/Cre approach in peripheral B cells of p53-deficient mice (referred to as “CXP” mice) leads to surface Ig-negative peripheral B cell lymphomas24,25. CXP B cell lymphomas arise from progenitors that delete or aberrantly rearrange their Igκ and Igλ light chain loci and routinely harbor a T(12;15) that fuses IgH S regions to sequences just upstream of c-myc, leading to high level c-myc expression from a translocated single copy c-myc gene25,26. Such T(12;15)s lack iEμ as they occur downstream of this element24. To test potential roles of the IgH3’RR in CXP tumorigenesis, we followed tumor development in cohorts of CXPR+/- and CXPR-/- mice. CXPR+/- mice succumbed to the same tumor spectrum as CXP mice25, with 40% developing surface Ig-negative B cell lymphomas that appeared identical to CXP B cell lymphomas (Fig. 2a and Supp. Table 2). The remaining CXPR+/- mice succumbed to thymic lymphomas or other tumors associated with germline p53 deficiency. In contrast, none of 17 analyzed CXPR-/- mice developed B cell lymphoma; instead, most died from thymic lymphoma (Fig. 2a and Supp. Table 2). Thus, homozygous IgH3’RR inactivation abrogates CXP B cell lymphomas.


Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region.

Gostissa M, Yan CT, Bianco JM, Cogné M, Pinaud E, Alt FW - Nature (2009)

Deletion of the IgH3’RR abrogates development of peripheral B cell lymphomasa. Left: Kaplan-Meier curve of the CXPR+/- (n=22) and CXPR-/- (n=17) cohorts. Curves represent total survival. Right: Percentage of mice in the CXPR+/- and CXPR-/- cohorts succumbing to B cell lymphomas, thymic lymphomas or to other cause of death. b. Southern blot analysis of CXPR+/- tumor DNA with probes indicated on the right of each panel. Numbers refer to individual mice in the cohort (see Supp. Table 2). K, kidney, used as control; Tu, tumor. A schematic of the c-myc locus, indicating the 5’ and 3’ probes used to detect c-myc rearrangements is on the top.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2802177&req=5

Figure 2: Deletion of the IgH3’RR abrogates development of peripheral B cell lymphomasa. Left: Kaplan-Meier curve of the CXPR+/- (n=22) and CXPR-/- (n=17) cohorts. Curves represent total survival. Right: Percentage of mice in the CXPR+/- and CXPR-/- cohorts succumbing to B cell lymphomas, thymic lymphomas or to other cause of death. b. Southern blot analysis of CXPR+/- tumor DNA with probes indicated on the right of each panel. Numbers refer to individual mice in the cohort (see Supp. Table 2). K, kidney, used as control; Tu, tumor. A schematic of the c-myc locus, indicating the 5’ and 3’ probes used to detect c-myc rearrangements is on the top.
Mentions: Specific inactivation of Xrcc4 by a loxP/Cre approach in peripheral B cells of p53-deficient mice (referred to as “CXP” mice) leads to surface Ig-negative peripheral B cell lymphomas24,25. CXP B cell lymphomas arise from progenitors that delete or aberrantly rearrange their Igκ and Igλ light chain loci and routinely harbor a T(12;15) that fuses IgH S regions to sequences just upstream of c-myc, leading to high level c-myc expression from a translocated single copy c-myc gene25,26. Such T(12;15)s lack iEμ as they occur downstream of this element24. To test potential roles of the IgH3’RR in CXP tumorigenesis, we followed tumor development in cohorts of CXPR+/- and CXPR-/- mice. CXPR+/- mice succumbed to the same tumor spectrum as CXP mice25, with 40% developing surface Ig-negative B cell lymphomas that appeared identical to CXP B cell lymphomas (Fig. 2a and Supp. Table 2). The remaining CXPR+/- mice succumbed to thymic lymphomas or other tumors associated with germline p53 deficiency. In contrast, none of 17 analyzed CXPR-/- mice developed B cell lymphoma; instead, most died from thymic lymphoma (Fig. 2a and Supp. Table 2). Thus, homozygous IgH3’RR inactivation abrogates CXP B cell lymphomas.

Bottom Line: Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations.We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations.As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

Show MeSH
Related in: MedlinePlus