Therapeutic implication of concomitant chromosomal aberrations in patients with aggressive B-cell lymphomas

Abstract

A subset of diffuse large B-cell lymphomas (DLBCL) harbors concomitant rearrangements of MYC, BCL2 and BCL6 and is characterized by clinical aggressiveness and intrinsic refractoriness to standard chemoimmunotherapy. Commonly identified as "double or triple hit" lymphomas, these diseases represent a therapeutic challenge to chemotherapy-based regimens and likely require a more targeted approach. Herein we summarize the unique biological behavior of double and triple hit lymphomas focusing on the coordinated network of pathways that enable cancer cells to tolerate the oncogenic stress imposed by the co-expression of MYC, BCL2 and BCL6. We discuss how these enabling pathways contribute to the chemorefractoriness of these tumors. We propose to exploit lymphoma cells' addiction to these oncogenic networks to design combinatorial treatments for this aggressive disease based on the modulation of epigenetically-silenced pathways and decreasing expression and activity of these oncogenic drivers.

PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas

“…Double-hit lymphoma (DHL) is a subgroup of aggressive B cell lymphoma originally defined as having both MYC and BCL2 chromosomal translocations, which have a rapidly progressing clinical course, are refractory to aggressive treatment, and have short survival (5,6). Over time, the definition of DHL was expanded to include diffuse large B cell lymphoma (DLBCL) having MYC trans-location combined with translocations involving either BCL2 or BCL6 as well as DLBCL that cooverexpress MYC and BCL-2 oncoproteins via other means (double-protein-expression lymphomas [DELs]) (6,7).…”

“…Double-hit lymphoma (DHL) is a subgroup of aggressive B cell lymphoma originally defined as having both MYC and BCL2 chromosomal translocations, which have a rapidly progressing clinical course, are refractory to aggressive treatment, and have short survival (5,6). Over time, the definition of DHL was expanded to include diffuse large B cell lymphoma (DLBCL) having MYC trans-location combined with translocations involving either BCL2 or BCL6 as well as DLBCL that cooverexpress MYC and BCL-2 oncoproteins via other means (double-protein-expression lymphomas [DELs]) (6,7). Overall, approximately 20%-30% of DLBCLs overexpress both MYC and BCL-2 or have MYC and BCL2 gene rearrangements, and with standard therapy for non-Hodgkin lymphoma (e.g., R-CHOP), both DHL patient types have a worse prognosis than patients without these alterations, with median OS of only 5 to 24 months (8,9).…”

“…Overall, approximately 20%-30% of DLBCLs overexpress both MYC and BCL-2 or have MYC and BCL2 gene rearrangements, and with standard therapy for non-Hodgkin lymphoma (e.g., R-CHOP), both DHL patient types have a worse prognosis than patients without these alterations, with median OS of only 5 to 24 months (8,9). Given that both DHL and DEL share a rapidly progressing clinical course, are refractory to treatment, and are currently considered incurable, we included both of these germinal center-originated large B cell lymphomas subtypes (6,7,(10)(11)(12)(13)(14)(15) in our analyses and have designated both types as DHL in this study.…”

HSP110 sustains chronic NF-κB signaling in activated B-cell diffuse large B-cell lymphoma through MyD88 stabilization

“…Interestingly, a body of literature has highlighted the fact that tumor cells acquire a biological addiction to heat shock proteins (HSPs) and stress proteins during malignant transformation. [3][4][5] HSPs are highly conserved molecular chaperone proteins whose expression is induced in response to multiple physiological and environmental stresses. 6 In these contexts, they control a large array of cellular functions to rescue the cell from debilitating conditions.…”

“…11 In particular, in lymphoma, HSP90 has been shown to have multiple roles in key DLBCL oncogenic pathways. Indeed, its capacity to enhance B-cell-like 6 (BCL6) oncogenesis 4 and to interact with and stabilize key B-cell receptor (BCR) protein complexes (CD79A/B-SYK-BTK-PLCg2) 3 suggests that targeting HSP90 could represent an interesting additional option for treating DLBCL. Unfortunately, a recent clinical trial using the HSP90 inhibitor AUY922 in DLBCL (NCT01485536) was halted early because of limited response and adverse effects in 100% of patients, prompting the search for other potential targets.…”