Immunomodulatory cytokines control the expression of a leukemic state in a de novo model of MYC-induced human AML

Human acute myeloid leukemias (AMLs) comprise a genetically and biologically diverse group of clonal hematologic malignancies. Nevertheless, they all share the defining features of deregulated growth and a blockade of normal terminal differentiation events. Hematopoietic stem cells appear to be the origin of clones from which human AML may often arise, but the intrinsic and extrinsic processes that establish self-sustaining, overtly leukemic human cell populations remain poorly understood, exacerbated by historical difficulties in developing de novo models of AML in human cells and drawbacks inherent in analyzing leukemic cells obtained from patients or model organisms. The finding that MYC expression is commonly increased in AML cells carrying different upstream driver mutations led us to examine the effects of forcing a modestly enhanced level of expression of this gene in freshly isolated human CD34+ hematopoietic cells. We now show that both early and late types of cells with granulopoietic potential when transduced with a MYC-encoding lentiviral vector produce a rapidly fatal, phenotypically and transcriptionally indistinguishable, serially transplantable AML at high efficiency in immunodeficient mice, but only in recipients that are producing human interleukin-3 (IL3) and/or granulocyte-macrophage colony-stimulating factor (GM-CSF). In the absence of these human growth factors (GFs), transplants of MYC-transduced CD34+ cells regenerate a normal spectrum of human lymphoid and myeloid progeny. However, upon secondary transfer to human GF-producing mice, they produce a phenotypically similar, rapidly fatal AML. The unique features of this model that include the reproducible creation of a latent AML program in primary human cells that is rapidly activated by inflammatory growth factors portend its utility as a powerful new platform for elucidating critical shared molecular mechanisms responsible for creating aggressive human myeloid leukemias. bulk RNA-seq: 6 AML generated in NRG-3GS mice by injecting CD34+CD38- or GMP cord blood cells lentivirally transduced with a vector carrying the cDNA for MYC. At Euthanasia, bone marrow or spleen cells were flow sorted for humanCD33 and GFP prior to RNA extraction. single cell RNA-seq: 4 AML generated in NRG-3GS mice by injecting CD34+CD38- or GMP cord blood cells lentivirally transduced with a vector carrying the cDNA for MYC. At Euthanasia, spleen cells were flow sorted for human CD33 and GFP prior to RNA extraction.