Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia

Abstract

A challenge for the development of therapies selectively targeting leukemic stem cells in acute myeloid leukemia (AML) is their similarity to normal hematopoietic stem cells (HSCs). Here we demonstrate that the leukemia-propagating cell in murine CALM/AF10-positive AML differs from normal HSCs by B220 surface expression and immunoglobulin heavy chain rearrangement. Furthermore, depletion of B220+ cells in leukemic transplants impaired development of leukemia in recipients. As in the murine model, human CALM/AF10-positive AML was characterized by CD45RA (B220)-positive, IG DH-JH rearranged leukemic cells. These data demonstrate in a murine leukemia model that AML can be propagated by a transformed progenitor with lymphoid characteristics, which can be targeted by antibodies that do not crossreact with normal HSCs.

Hox genes in hematopoiesis and leukemogenesis

“…Consistent with the hypothesis that Hox genes drive the self-renewal program in LSCs of any origin, Hoxa gene expression was elevated in these lineage positive LSCs. Similarly, it has been shown that the LSC in murine CALM/AF10-positive AML was positive for the lymphoid associated surface antigen B220, raising the possibility that the LSC in a subset of AMLs is a lymphoid progenitor or a myeloid progenitor with lymphoid characteristics (Deshpande et al, 2006). Although the level of Hox gene expression was not reported in these lineage-positive LSCs, it would be of interest to determine if their novel ability to self-renew is a result of dysregulation of Hox gene expression, more precisely, genes of the Hoxa cluster.…”

The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation

“…Both populations generated an identical phenotype as compared with the primary leukemia with AML without signs of differentiation and full infiltration of lymph nodes, spleen and liver (Figures 6e and f). On the basis of the findings that in some murine leukemia models L-ICs were found in the B220 þ population, 25 we also sorted for Flk2 and B220 expression and inoculated 2000 of these cells into sublethally irradiated mice. We found that cells from all populations originated leukemia, but the B220 À population not expressing Flk2 gave rise to leukemia in a time frame close to that of common myeloid/GMP or HSC (Figure 6c).…”

The role of CALM–AF10 gene fusion in acute leukemia

“…[39][40][41][42][43][44][45] Interestingly, most of the AML M0, M1 and M2 cases that have been analyzed show clonal IGH, TCRG and/or TCRD gene rearrangements, suggesting that the target for malignant transformation may have been a multipotential hematopoietic precursor cell. 38,46 CALM-AF10 translocations have been identified in both children and adults with AML; specific lesions include splenomegaly, hepatomegaly, mediastinal masses and CNS leukemia. 47 Cytochemical and immunophenotypic data vary with the diagnosis but include markers for lymphoid as well as myeloid antigens.…”

“…51 A second study used retroviral transduction and bone marrow transplantation to generate acute leukemia in mice. 46 Recipient mice transplanted with bone marrow cells that expressed a CALM-AF10 fusion gene, developed disease a median of 110 days following transplantation. Mice with leukemia were anemic and had circulating blasts.…”

“…Interestingly, these authors went on to show that AML could be propagated from a leukemic cell with lymphoid features, as Mac1 þ myeloid leukemia could be established by serial transplantation of Mac1 þ /B220 þ or Mac1À/B220 þ leukemia cells. 46 A third recent study reported a CALM-AF10 transgenic mouse model that developed acute leukemia after a long latency period with incomplete penetrance. 52 In this study, a CALM-AF10 cDNA was expressed under Vav regulatory elements in the hematopoietic compartment, including thymus, spleen and bone marrow.…”