title: CD93 Marks a Non-Quiescent Human Leukemia Stem Cell Population and Is Required for Development of MLL-Rearranged Acute Myeloid Leukemia.
abstract: Leukemia stem cells (LSCs) are thought to share several properties with hematopoietic stem cells (HSCs), including cell-cycle quiescence and a capacity for self-renewal. These features are hypothesized to underlie leukemic initiation, progression, and relapse, and they also complicate efforts to eradicate leukemia through therapeutic targeting of LSCs without adverse effects on HSCs. Here, we show that acute myeloid leukemias (AMLs) with genomic rearrangements of the MLL gene contain a non-quiescent LSC population. Although human CD34(+)CD38(-) LSCs are generally highly quiescent, the C-type lectin CD93 is expressed on a subset of actively cycling, non-quiescent AML cells enriched for LSC activity. CD93 expression is functionally required for engraftment of primary human AML LSCs and leukemogenesis, and it regulates LSC self-renewal predominantly by silencing CDKN2B, a major tumor suppressor in AML. Thus, CD93 expression identifies a predominantly cycling, non-quiescent leukemia-initiating cell population in MLL-rearranged AML, providing opportunities for selective targeting and eradication of LSCs.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Liedtke
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: mcleary@stanford.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
mesh_terms: D014408:Biomarkers, Tumor; D000066673:Cell Self Renewal; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D015321:Gene Rearrangement; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000209:etiology* / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D054503:Lymphoid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011951:Receptors, Complement / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; C032402:complement 1q receptor; D051788:Myeloid-Lymphoid Leukemia Protein
keywords: CD93; CDKN2B; MLL; leukemia stem cells