A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia

Abstract

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABLgene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABLp190 and BCR-ABLp210, are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph1-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph1-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia–initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph1-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34+CD38−, which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph1-ALL.

Acute B lymphoblastic leukaemia‐propagating cells are present at high frequency in diverse lymphoblast populations

“…Following passage through the mice, the frequency of LPCs was even higher (1:10) and all primograft specimens engrafted with as few as 10 transplanted cells. These are much higher frequencies than reported in previous studies, where less immunodeficient SCID or NOD/ SCID mice engrafted with 10,000-100,000 cells (Castor et al, 2005;Cobaleda et al, 2000;Cox et al, 2004;Hong et al, 2008;le Viseur et al, 2008). This study confirms that in many B-ALL patients, the frequency of blasts that are able to contribute to and re-grow the leukaemia is likely to be high and that the ability for clonal expansion may not be limited to a rare stem-like population.…”

“…The differences between our model, suggesting a lack of a leukaemia stem cell hierarchy, and previous studies suggesting the presence of a distinct leukaemic stem cell population (Cobaleda et al, 2000;Cox et al, 2004Cox et al, , 2009Hong et al, 2008) are most likely due to differences in the mouse models. Taussig and co-workers demonstrated that even in severely immunodeficient mice, antibody-coated human cells can be cleared by the residual innate immune system (Taussig et al, 2008).…”

Philadelphia chromosome‐positive mature B‐cell (Burkitt cell) leukaemia

“…The occurrence of a Ph + Burkitt's leukaemia might reflect multiple-step cancer development, and gives room to speculation about leukaemogenesis in an in vivo model. As a leukaemia-initiating genetic event in Ph + -ALL might occur at the stem cell level (Cobaleda et al, 2000) and myc activation plays a permissive role for the transforming activity of the bcr-abl fusion product (Sawyers et al, 1992), it can be speculated that a possibly silent Ph + clone had been transformed into Burkitt's leukaemia by an unidentified second hit in the present case. This interpretation, taken as a model, would also explain the transformation into blast phase in chronic myeloid leukaemia (CML).…”

Contribution of GATA1 dysfunction to multi‐step leukemogenesis

“…(28) Subsequently, a number of reports have provided evidence that LSCs accumulate in the CD34 + CD38 À subpopulation in cases of acute myelogenous leukemia and acute lymphocytic leukemia. (29)(30)(31)(32) Normal hematopoietic stem cells (HSCs) also exhibit the Lin À CD34 + CD38 À phenotype, (33) and thus, it has been proposed that HSCs are the most likely target for transformation into LSCs. In contrast, recent reports have clarified that additional subpopulations of LSCs may exist in some cases.…”