Acute myeloid leukaemia (KEGG map)

The KEGG acute myeloid leukaemia map (hsa05221) draws the classic two-hit model of AML. The first hit is disordered growth and survival signalling: internal tandem duplications or point mutations in the receptor tyrosine kinase FLT3, mutations in KIT, and mutations in NRAS or KRAS. These feed three downstream routes, RAS to RAF to MEK to ERK, PI3K to AKT to mTOR, and STAT5, which together drive proliferation and switch off apoptosis. The second hit is a block in myeloid differentiation caused by transcription factor fusions created by chromosomal translocations, AML1-ETO (RUNX1-RUNX1T1) from t(8;21), PML-RARA from t(15;17) and PLZF-RARA, which recruit co-repressors and silence the genes that CEBPA, PU.1 and RUNX1 would normally switch on to make mature granulocytes and monocytes. In other cases CEBPA or RUNX1 themselves are mutated. The review by Döhner et al., N Engl J Med, 2015 (doi:10.1056/NEJMra1406184) frames the same biology in terms of recurrently mutated gene classes (signalling genes, myeloid transcription factors, NPM1, DNA methylation and chromatin genes, and the spliceosome) and notes that FLT3-ITD predicts shorter survival while CEBPA biallelic mutation and NPM1 mutation without FLT3-ITD are favourable.

What drugs do about it: the FLT3 inhibitors midostaurin (with induction chemotherapy), gilteritinib and quizartinib switch off the first hit in FLT3-mutant AML. The PML-RARA differentiation block is reversed by all-trans retinoic acid plus arsenic trioxide, which degrade the fusion protein and cure most acute promyelocytic leukaemia without cytotoxic chemotherapy. Venetoclax with azacitidine targets the BCL2 survival dependency that sits downstream of these signals in older or unfit patients.