Clonal Chromosomal Abnormalities Showing Multiple-Cell-Lineage Involvement in Acute Myeloid Leukemia

Abstract

To determine whether one or more hematopoietic-cell lineages are involved in acute myeloid leukemia (AML), we designed a technique that simultaneously identifies a cell as malignant and determines its lineage. We used numerical clonal chromosomal abnormalities, which are readily detected, to indicate neoplasia, and monoclonal antibodies in an alkaline phosphatase-antialkaline phosphatase detection procedure to identify lineages as granulocytic-monocytic, erythrocytic, or megakaryocytic. Examination of bone marrow from 12 patients with AML showed metaphases of granulocytic-monocytic lineage with abnormal karyotypes in all patients. In seven patients, we also detected abnormal karyotypes in the erythrocytic or megakaryocytic lineage. In all four patients with monosomy 7, both granulocytic-monocytic and erythrocytic cells were affected. Two of four patients with trisomy 8 also had evidence of multiple-lineage involvement, but in two the erythrocytic lineage had normal karyotypes, suggesting an origin at a progenitor-cell stage committed to granulocytic-monocytic development. Multiple-lineage involvement was found in AML both arising de novo (four of five analyzable cases) and following another cancer (three of four analyzable cases). These data demonstrate multiple-lineage involvement in a high proportion of cases of AML and suggest that many cases originate from the multipotent hematopoietic cell or from an earlier progenitor cell.

Concepts of human leukemic development

“…The results of their studies were conflicting, with some patients showing the same skewed (nonrandom) XCIP in their leukemic blasts as well as in erythroid cells, platelets, and in one case B lymphoid cells, while other patients seemed to have involvement of only the granulocytic/monocytic lineages. Similar findings were reported in an additional study assessing karyotypic abnormalities in bone marrow cells from AML patients stained with lineage antibodies (Keina¨nen et al, 1988). Together, these data suggest that AML is a heterogeneous disease, originating in some cases from a primitive multipotential cell, and in other cases from a committed progenitor restricted to granulocytic/monocytic differentiation.…”

Unique molecular and cellular features of acute myelogenous leukemia stem cells

“…1,2 Consequently, as is observed for normal hematopoiesis, LSCs lie at the root of clonal growth and are therefore thought to be responsible for perpetuation of the leukemic population. While the general concept of LSCs is well-established, [3][4][5][6][7][8][9] a formal description of stem cells in AML has only come about as the result of relatively recent studies. Primarily through the efforts of John Dick and colleagues, a specific initial phenotype (CD34 + /CD38 − ) was assigned to the AML stem cell, and the characteristics of this population were defined by transplantation studies using the xenogeneic NOD/SCID mouse model system.…”

Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model

“…Generally, these leukemic cells are committed to the myelo-monocytic lineage although they might also show erythroid or megakaryocytic lineage charac- teristics. Analysis of clonal markers [1][2][3] has shown that leukemic transformation may occur at the level of the pluripotent or the less primitive, committed, hematopoietic stem/ progenitor cell. We and others have recently shown that these primitive leukemic progenitors can give rise to long-term malignant hemopoiesis in vitro when supported by a feeder of murine stromal cells.…”