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Lymphoma research is a paradigm of integrating basic and applied research within the fields of molecular marker-based diagnosis and therapy. In recent years, major advances in next-generation sequencing have substantially improved the understanding of the genomics underlying diffuse large B-cell lymphoma (DLBCL), the most frequent type of B-cell lymphoma. This review addresses the various approaches that have helped unveil the biology and intricate alterations in this pathology, from cell lines to more sophisticated last-generation experimental models, such as organoids. We also provide an overview of the most recent findings in the field, their potential relevance for designing targeted therapies and the corresponding applicability to personalized medicine.
Strategy |
Phenotype/Incidence |
Prospective Uses |
|
---|---|---|---|
Genetically engineered mice |
Eμ-Myc |
DLBCL (time dependent) [70] |
|
Eμ-BRD2 |
DLBCL [61] |
||
Bcl6 Knock in |
GC-DLBCL [62] |
||
Bcl6/Myc |
ABC-DLBCL [62] |
||
Iµ:HA.BCL6 |
36–62% lymphoma incidence [62] |
Combination with conditional Spen and Tnfaip3 knockout or oncogenic Notch2 alleles to model Cluster BN2 |
|
Mb1:Cre;Eµ:Bcl2;Crebbpfl/fl |
GC-DLBCL [71] |
Combination of the different alleles to generate a sophisticated EZB mouse model |
|
Cγ1Cre/wt;Kmt2dfl/fl;VavP:Bcl2 |
21% incidence GC-DLBCL [72] |
||
Ezh2cond.p.Y641F/wt;VavP:Bcl2; Cγ1Cre/wt |
DLBCL-like lymphoma [73] |
||
Cd19Cre/wt;Myd88cond.p.L252P/wt;Rosa26LSL.BCL2-IRES-GFP/wt |
85% incidence ABC-DLBCL [74] |
Modeling of the MCD cluster by combination of both alleles and a newly generated CD79Bcond.p.Y196H/wt allele, or with the already existing Prdm1fl/fl |
|
Cγ1Cre;Prdm1fl/fl;Rosa26LSL.IKK2ca |
50% incidence IRF4, post-GC DLBCL [75] |
||
Syngeneic models |
Pi-BCL1 (m) iv or ip in BALB/c immunocompetent mice |
Gene editing Generation of complex organoids prior to inoculation of the cell line |
|
A20 (m) iv, intrasplenic, or sc injection in BALB/c immunocompetent mice |
|||
Xenograft models |
SU-DHL-4 (h) iv or sc in SCID immunodeficient mice |
Gene editing Generation of organoids Inoculation in humanized NOD/SCID mice |
|
Transduced HPCs in irradiated mice |
Generation of a-la-carte HPCs reproducing the genetic signatures Inoculation in humanized NOD/SCID mice |
||
PDX iv or sc in immunodeficient mice |
20–30% successful engraftment |
Use of humanized mice to study lymphoma physiology and drug responses Personalized medicine |
|
PDO iv or sc in immunodeficient mice |
20–30% successful engraftment |
Genetic modification Use of humanized mice to study lymphoma physiology and drug responses Personalized medicine. |
The headings of each mouse model subtype are highlighted in bold.