New Gene Expression Atlas Reveals AML Heterogeneity and Differentiation Pathways

A comprehensive gene expression atlas, developed using single-cell RNA sequencing data, has mapped normal blood cell development and identified how disrupted differentiation drives acute myeloid leukemia (AML). Presented at the AACR Annual Meeting 2025 and published in Blood Cancer Discovery, the study analyzed over 1.2 million leukemia cells from 318 patients to catalog AML’s diverse cell states and their genetic drivers.

Led by Andy Zeng, MD/PhD student at the University of Toronto, and senior author John E. Dick, the team first constructed a reference atlas of normal hematopoiesis using 263,519 hematopoietic stem and progenitor cells. This baseline enabled precise comparison with leukemia cells, revealing at least 12 distinct differentiation patterns in AML. Some patterns overlapped with rare leukemias like mixed-phenotype acute leukemia (MPAL) and acute erythroid leukemia (AEL), highlighting diagnostic ambiguities. 

“This represents an important step in evaluating cell state heterogeneity within and across AML patients in a more quantitative way,” said Zeng. The study emphasized that AML’s heterogeneity stems not only from genetic mutations but also from cellular context. For example, identical mutations produced different leukemia subtypes depending on the cell of origin or coexisting mutations.

By correlating bulk RNA sequencing data from 1,200+ AML samples with cell states, researchers found that genetic drivers interact with cellular environments to shape disease biology. “These findings reveal that the phenotypic heterogeneity in AML arises from the interplay between genetic drivers and the specific cellular context, helping us begin to decipher the ‘rules’ governing the factors that shape the disease,”  Zeng explained.

The atlas provides a toolkit for researchers to analyze AML samples, linking cell states to genetic and clinical variables. Zeng hopes this will uncover biomarkers to improve prognosis prediction and precision therapies. “By establishing a high-resolution single-cell reference atlas of hematopoiesis, we’ve not only advanced our understanding of how differentiation goes awry in AML, but we’ve also provided an accessible toolkit for other researchers to rapidly map and classify their own blood samples profiled by single-cell RNA sequencing.”