Potential way to combat acute myeloid leukemia

Numerous genetic alterations have been identified in tumor samples from individuals with acute myeloid leukemia (AML). But the translation of these discoveries into clinical practice has remained a big challenge. This is largely because different patients may have different mutations in their tumors, and even in the same patient, different cancer cells may carry different mutations. Some of the mutations observed in AML cells are also present in people without AML. All these make it difficult to determine exactly which mutations contribute to AML development.

Now, a team of researchers from RIKEN Center for Integrative Medical Sciences in Japan and Dana-Farber Cancer Institute in the USA has found a method to solve this problem. In the method, immunosuppressed mice are used to study how AML cells behave in diverse tissues.

In the study, the team isolated subsets of leukemic cells with specific mutations from AML patients, and examined the cells' ability to induce cancer in immunosuppressed mice. This method, combined with genomic analyses, enabled the team to find that a mutation in the FLT3 gene, called FLT3-ITD, is associated with the transformation of normal bone marrow cells to AML cells, and that the BCL2 gene confers drug resistance in FLT3-mutated AML.

FLT3 encodes a protein called fms-like tyrosine kinase 3, and the FLT3 signaling is critical for the normal development of haematopoietic stem cells. FLT3 is often mutated in AML, and the mutation FLT3-ITD correlates with poor outcome and aggressive tumors.

In the further experiments, the team discovered that RK-20449, a compound that inhibits haematopoietic cell kinase, is good at suppressing the abnormal signaling induced by FLT3-ITD and eliminating AML cells. Moreover, combining RK-20449 with another drug, ABT-199, led to better therapeutic effect in mice transplanted with AML cells. ABT-199 (Venetoclax) is a potent BCL-2 inhibitor and is used in the treatment for chronic lymphocytic leukemia.

The results show that co-inhibition of multiple signaling pathways involved in cancer would be a potential way to combat AML and other diseases that harbor numerous and diverse genetic alterations.

Findings of the study are described in a paper titled "Overcoming mutational complexity in acute myeloid leukemia by inhibition of critical pathways," appearing in Science Translational Medicine on 25 Oct. 2017.
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