AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation

AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation

Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305

Contributed by Irving L. Weissman

Abstract

Leukemia-specific AML1/ETO transcripts are detectable in most patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. To understand the inconsistency between the clinical cure and the presence of “residual disease” at a molecular level, we separated and identified the cells expressing AML1/ETO by phenotype and function. Here we demonstrate that AML1/ETO transcripts are present in a fraction of stem cells, monocytes, and B cells in remission marrow, and in a fraction of B cells in leukemic marrow, but not in T cells. AML1/ETO transcripts also were demonstrated in a fraction of colony-forming cells of erythroid, granulocyte-macrophage, and/or megakaryocyte lineages in both leukemic and remission marrow. These data strongly suggest that the acquisition of the t(8;21) occurs at the level of stem cells capable of differentiating into B cells as well as all myeloid lineages, and that a fraction of the AML1/ETO-expressing stem cells undergo additional oncogenic event(s) that ultimately leads to transformation into AML.

Footnotes

↵ * To whom reprint requests should be sent at present address: Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Sm 770B, 44 Binney Street, Boston, MA 02115. E-mail: Koichi_akashi{at}dfci.harvard.edu.
Abbreviations:

AML,

acute myelogenous leukemia;

HSC,

hematopoietic stem cells;

MBT,

mobilized blood transplantation;

RT-PCR,

reverse transcriptase–PCR;

BFU-E,

burst-forming unit-erythroid;

CFU-Meg,

colony-forming unit-megakaryocytes;

CFU-GM,

colony-forming unit granulocyte/macrophages;

BM,

bone marrow;

Lin,

lineage;

CLP,

common lymphoid progenitors;

MPO,

myeloperoxidase;

EBV,

Epstein–Barr virus