Session: 618. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Translational Research, Diseases, Lymphoid Malignancies
Using a co-culture approach with human bone marrow-derived mesenchymal stromal cells (MSCs) and media optimized for growth of lymphoid and myeloid lineages, we were able to expand and monitor primary MLL-r patient material for more than three weeks. Primary material from two MPAL patients and their lymphoid and myeloid subpopulations were analyzed for their drug responses including immunophenotypic and global transcriptomic characterization.
We observed a dramatic loss of cell numbers in response to SNDX-5613, with the IC50 value ranging from 80 to 800nM. Similar analyses of the sorted fractions revealed that the observed loss of cell numbers is mainly caused by the reduction of the lymphoid subfraction. Immunophenotypic analyses showed that surviving cells within both lymphoid and myeloid fractions are losing CD34 with simultaneous gain of the CD38 marker, suggesting cellular maturation. Treatment of the lymphoid fraction with SNDX-5613 caused a dose-dependent loss of the CD19+CD33+ cell population and a simultaneous gain of CD19+CD33-, and CD19-CD33+ cells. These data suggest the cellular origin of the myeloid fraction to be residing within the lymphoid counterpart. Interestingly, myeloid cells responded to Menin-MLL inhibition with increased surface expression of monocytic markers (e.g. CD11b, CD14, CD15), elevated RNA expression of genes involved in cell adhesion and morphological changes, indicating myeloid differentiation of the surviving cells. Moreover, transcriptomic analysis of the lymphoid subfraction revealed dose-dependent increase of the MS4A1 gene expression (encoding for CD20) suggesting simultaneous lymphoid maturation of the CD19+ proB-like blasts.
In conclusion, our study shows that Menin-MLL inhibition drives both myeloid differentiation and lymphoid maturation in MLL-r MPALs. These myeloid data are consistent with observations of differentiation syndrome as an on-target effect in current clinical trials while the phenotypic changes in the lymphoid cells are new findings. Together, these data strongly suggests that MLL-r MPAL patients could benefit from the inclusion of the Menin-MLL1 inhibitors into their treatment regimens.
Disclosures: No relevant conflicts of interest to declare.
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