APOE ε4 Allele Frequency Among Cognitively Healthy Members of an Ojibwe Tribal Nation.

Objectives: APOE ε4 frequency varies by geography and ancestry. We provide data regarding the frequency of this allele in the Ojibwe people, the fifth largest Indigenous people in the United States. Methods: Population study including 33 cognitively normal older individuals of an Ojibwe Tribal Nation (total population: 984; all with ≥25% Ojibwe ancestry). Results: APOE ε4 allele frequency was 19.7%, which is comparable with other cognitively normal American Indian, Alaskan Native, and non-Hispanic White populations of the United States and Europe, with the exception of a lower frequency among Choctaw Nation of Oklahoma participants with >50% American Indian ancestry. Discussion: While some global populations have very low APOE ε4 prevalence, this allele appears common among American Indian Tribal Nations included thus far in the United States. Because APOE ε4 is a cornerstone for novel diagnostics and therapeutics for Alzheimer disease (AD), future study is warranted to understand ancestry-dependent effects of APOE ε4 on AD risk and biology.

Single-Cell Gene Expression Analyses Reveal Distinct Self-Renewing and Proliferating Subsets in the Leukemia Stem Cell Compartment in Acute Myeloid Leukemia.

Standard chemotherapy for acute myeloid leukemia (AML) targets proliferative cells and efficiently induces complete remission; however, many patients relapse and die of their disease. Relapse is caused by leukemia stem cells (LSC), the cells with self-renewal capacity. Self-renewal and proliferation are separate functions in normal hematopoietic stem cells (HSC) in steady-state conditions. If these functions are also separate functions in LSCs, then antiproliferative therapies may fail to target self-renewal, allowing for relapse. We investigated whether proliferation and self-renewal are separate functions in LSCs as they often are in HSCs. Distinct transcriptional profiles within LSCs of Mll-AF9/NRASG12V murine AML were identified using single-cell RNA sequencing. Single-cell qPCR revealed that these genes were also differentially expressed in primary human LSCs and normal human HSPCs. A smaller subset of these genes was upregulated in LSCs relative to HSPCs; this subset of genes constitutes "LSC-specific" genes in human AML. To assess the differences between these profiles, we identified cell surface markers, CD69 and CD36, whose genes were differentially expressed between these profiles. In vivo mouse reconstitution assays resealed that only CD69High LSCs were capable of self-renewal and were poorly proliferative. In contrast, CD36High LSCs were unable to transplant leukemia but were highly proliferative. These data demonstrate that the transcriptional foundations of self-renewal and proliferation are distinct in LSCs as they often are in normal stem cells and suggest that therapeutic strategies that target self-renewal, in addition to proliferation, are critical to prevent relapse and improve survival in AML. SIGNIFICANCE: These findings define and functionally validate a self-renewal gene profile of leukemia stem cells at the single-cell level and demonstrate that self-renewal and proliferation are distinct in AML. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/458/F1.large.jpg.

Buccal epithelial cells display somatic, bone marrow-derived CALR mutation.

Buccal epithelial cells harbor an MPN-associated CALR mutation in a patient with CALR-mutant essential thrombocytosis, Ph+ CML, and no germ line CALR mutation.