Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies

Abstract

The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), JAK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3'JAK2-5'PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.

Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas

“…These translocations might also serve a dual purpose to abrogate expression of partner genes with tumor suppressor function (GET4, KIAA0226L, PTPN1) similarly to CIITA 59 SRs ( Figure 5). 5,[19][20][21][22][23] Furthermore, 59 PDL translocations have been previously demonstrated to confer an immuneprivilege phenotype in the context of T-cell activation. 5 The 9 translocations occurring outside of CBR1 and CBR2 (5 of which are newly reported here) are a mixture of 59 and 39 events distributed across the PDL region, which we define here as a third category of translocations.…”

“…These events add to 6 intrachromosomal rearrangements that have been previously observed in immune-privilege lymphomas. 7,16,23 The functional effects of these rearrangements on both PDLs by IHC suggest that an increase in ligand expression is achieved through deletion of 39 UTRs and duplications of 1 or both PDL genes. 7 Our coculturing experiments using engineered cells, which are representative of duplications (wild-type PDCD1LG2-expressing DOHH-2) and 39 deletions (PDCD1LG2-IGHV7-81-expressing DOHH-2 cells, because this fusion results in the loss of the 2 terminal 39 PDCD1LG2 exons), provide additional support for this observation.…”

Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma

“…Like classical Hodgkin lymphoma, PMBCL frequently exhibits 9p24.1/PD-L1/PD-L2 copy-number alterations and rearrangements and associated PD-L1 and/or PD-L2 overexpression, potentially facilitating immune evasion. [7][8][9][10][11] The genetics of PMBCL could thus make it particularly susceptible to PD-1 blockade. 11 Pembrolizumab is a humanized anti-PD-1 monoclonal antibody blocking interaction of PD-1 with its ligands, PD-L1 and PD-L2.…”

“…[7][8][9][10][11] The genetics of PMBCL could thus make it particularly susceptible to PD-1 blockade. 11 Pembrolizumab is a humanized anti-PD-1 monoclonal antibody blocking interaction of PD-1 with its ligands, PD-L1 and PD-L2. Pembrolizumab has demonstrated efficacy against solid tumors 12,13 and promising antitumor activity in Hodgkin lymphoma.…”

Immune Checkpoint Inhibitors in the Treatment of Lymphomas

“…При ПМВКЛ, которая обладает многими гистологическими и генетическими характеристиками, сходными с кЛХ, нередко встречаются хромосомные аномалии с вовлечением 9p24.1, включая амплификацию и транслокацию данного локуса [20,[34][35][36]. Исследование гистологической структуры ПМВКЛ Ингибиторы иммунных контрольных точек в терапии лимфом показало, что в 72 % образцов выявлялась экспрессия PD-L2 и, в меньшей степени, PD-L1 на поверхности опухолевых клеток.…”