MYD88 mutation + CD79B mutation

PIM1 mutations did not affect the proliferation of DLBCL cells and did not increase resistance to doxorubicin, excluding the proliferation rate or treatment resistance as a cause of the poor prognosis associated with PIM1 mutations...Finally, in transwell assays, PIM1 mutant cells exhibited markedly increased migratory potential. Taken together, these studies indicate that PIM1 mutants are not likely associated with differential drug responses, but rather facilitate tumor dissemination and are thus associated with inferior prognosis in DLBCL patients harboring PIM1 mutations.

These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

Mice carrying all four genetic lesions showed a greater than 50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCB as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.

Furthermore, based on new genetic classifications, co-mutations in MYD88 and CD79 (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. Enrollment in the Phase 1a portion of the KT413-DL-101 study is ongoing. NCT05233033.

Background: Based on new genetic classifications, co-mutations in MYD88 and CD79B (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. Preclinical studies highlight the potential of IRAKIMiDs as a therapeutic approach for the treatment of MYD88MT DLBCL. KTX-582 demonstrates preferential activity in MYD88MT ABC-DLBCL. Single agent venetoclax demonstrated varying potency in ABC-DLBCL cell lines, irrespective of MYD88 mutational status.

We explored the feasibility of using a combination of two common hotspot mutations in MYD88 and CD79B in PCNSL and PTL plasma samples to aid in diagnosis and disease monitoring. The data presented show that the value of ddPCR for hotspot mutations in plasma of PCNSL and PTL patients is limited.

The sensitivity of ibrutinib is further enhanced in lymphomas additionally expressing Cd79b p.Y195H, both in the Prdm1-deficient and the Prdm1-proficient model systems. We have established and characterized novel refined autochthonous mouse models of MCD/C5 DLBCL which serve as a preclinical tool to test novel therapeutic strategies in this sub-entity and pave the way to a deeper understanding of molecular mechanisms of pathogenesis, treatment response and resistance in highly aggressive DLBCL.