Creation Of Patient Derived AML Xenografts Displaying Distinct Phenotypes and Geneotypes

We have recently successfully engrafted leukemic cells from bone marrow of several AML patients into immunocompromised NOD/SCID mice. One of them, AM7577, was reported in the last year ASH¹. This model displayed typical aggressive AML disease of M5 subtype, which starts at bone marrow and gradually expand to peripheral (spleen, lymphonode and peripheral blood…). AM7577 also harbors interesting genotypes of mutations for IDH2-R140Q, FLT3-ITD, DNMT3A R882H and NPM1.

Our second AML PDX model, AM8096, was established similarly using bone marrow from a recurrent patient with AML-M2 disease. AML8096 displayed similarly aggressive disease and the same 100% mortality, including typical symptoms (BW loss, hunched, inactivity, labored breathing, ruffled coat and eventual mortality) and with abundant leukemic cells in bone, etc. The leukemic cells can serially be passed in mice with 100% take-rate and cause consistent disease (even with < 1e4 cells). This also creates a renewable and potentially unlimited source of leukemia cells. The leukemic cells in mice are identical to those of the original patient leukemic cells (CD45⁺, CD33⁺, CD13⁺, CD123⁺, and CD19^-. However, some aspects of disease presentations are vastly different from that of AM7577. First, the peripheral symptom is significant less characterized by lower leukemic counts in peripheral blood and only slightly enlarged spleen and smaller lymphonode. Second, the leukemic cell morphology is also rather different with AM8096 demonstrating less differentiated phenotype. Third, the genotype, in contrast to AM7577, is wild-types for all the above oncogenes. While we have not identified the likely leukemogenesis driver gene for this model, we are currently performing RNAseq of AM8096, along with AM7577, in order to explore the underlying molecular mechanisms that drive both diseases. In addition, we are also investigating the drug response to standard of care (SOC), as compared to those AM7577.

In summary, the two AML models could serve as useful experimental models to investigate the diverse leukemogenesis, including molecular mechanisms by genetic profiling. Ultimately, they can be used to help to identify new treatment strategies for AML.

1. Liu, e.a. A unique leukemia mouse model established from AML patient with IDH2 R140Q and FLT3-ITD mutations among other common AML mutations. ASH-2012 Annual Meeting (2012).