H3K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations
Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes have been shown to be initiating mutation in a variety of solid tumors. Despite the high prevalence of H3K27M mutations in pediatric glioblastoma proceeded by the loss of global H3K27me2/3, these mutations have not been studied in human hematological cancers. Using the H3.3K27M/I transgenes we studied the effects of the loss of H3K27me2/3 on normal and transformed hematopoietic cells. We identified oncogenic histone H3K27M/I mutations in human acute myeloid leukemia (AML) that led to a significant reduction of H3K27me2/3. The mutation profiles of H3K27M/I patients revealed that these lesions invariably co-occurred with RUNX1 alterations. Expression of H3.3K27M/I in an AML1-ETO9a driven mouse model resulted in accelerated in vitro proliferation and in vivo disease latency. The expression of H3.3K27M in human CD34+ umbilical cord blood cells led to a selective expansion of a primitive hematopoietic progenitor population, but was insufficient to drive leukemogenesis on its own. This demonstrates a collaboration between RUNX1 and loss of H3K27me2/3. In the context of RUNX1 alterations in AML, hypo-H3K27me3 accelerates disease progression. We conclude that H3K27me2/3 has a leukemia suppressive function in RUNX1 mutant and translocated AML. Our findings have the potential to inform the development of a targeted therapeutic strategy for the treatment of RUNX1mut AML patients.
Hematopoietic Stem Cells Acute Myeloid Leukemia H3.3 K27M/I Oncohistones RUNX1 Leucegene