Huacheng Luo, PhD

Acute myeloid leukemia (AML) is an aggressive and fatal hematologic malignancy characterized by malignant transformation of myeloid cells. The development of AML is associated with accumulation of acquired genetic and epigenetic events in the differentiation of hematopoietic stem/ progenitor cells (HSPCs). HOX loci- associated long noncoding RNA (lncRNA), HOTTIP, is specifically up-regulated in MLLr+ AML patients that account for up to 50% of infant and 10% of adult acute leukemia with very poor prognosis. The m6A writer complex METTL3/METTL14 is required for development and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Consistent with our findings that HOTTIP is overexpressed in MLLr+-driven AML, both METTL3 and METTL14 are overexpressed in AMLs, especially in MLL+ pediatric AML. Here, we found that AML blasts express higher mRNA levels of METTL3 and METTL14 than normal cells, and expression levels of METTL3 or METTL14 are correlated with poorer prognosis in AML patients. Moreover, the expression of METTL3 or METTL14 has a positive correlation with the expression of HOTTIP in AML patients from TCGA datasets. In this proposal, we will explore the role of m6A modification of HOTTIP lncRNA in hematopoiesis and leukemogenesis, and we anticipate that our studies will identify novel therapeutic targets for the treatment of AML disease.