Growth autonomy and lineage switching in BCR-ABL-transduced human cord blood cells depend on different functional domains of BCR-ABL

Abstract

The tyrosine kinase activity of p210 BCR-ABL is essential to its leukemogenic potential, but the role of other functional domains in primary human hematopoietic cells has not been previously investigated. Here we show that infection of normal human CD34 þ cord blood (CB) cells with a retroviral vector encoding p210 BCR-ABL rapidly activates a factor-independent phenotype and autocrine interleukin-3/granulocyte colonystimulating factor/erythropoietin production in the transduced cells. These changes are characteristic of primitive chronic myeloid leukemic (CML) cells and are important to the leukemogenicity of BCR-ABL-transduced murine hematopoietic stem cells. When BCR-ABL-transduced human CB cells were incubated with imatinib mesylate, an inhibitor of the p210 BCR-ABL kinase, or when human CB cells were transduced with a BCR-ABL cDNA lacking the SH2 domain (p210DSH2), factor independence was significantly reduced. In contrast, deletion of the SH2 domain had little impact on the p210 BCR-ABL kinase-dependent promotion of erythropoietic differentiation also seen immediately following the BCR-ABL transduction of primitive human CB cells, but not in naturally occurring CML. Thus, p210 BCR-ABL has distinct biological effects in primary human hematopoietic cells, which variably mimic features of human CML, and activation of these changes can show different dependencies on the integrity of the SH1 and SH2 domains of p210 BCR-ABL .

Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies

“…The latter showed that expression of IL-3 and G-CSF is rapidly activated in both primitive normal human and murine hematopoietic cells following the retrovirally mediated introduction of a BCR-ABL transgene. 20,43,44 This changing pattern of growth factor gene expression is also consistent with the acquisition by differentiating CML cells of an increasing sensitivity to IM under conditions where saturating levels of exogenous growth factors are not available, as might be anticipated to occur in vivo.…”

Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice

“…17,21,22,31,32 This suggests that the BCR/ABL1 and FGFR1 fusion genes, at least partly, mediate their leukemogenic effects in a similar manner. In agreement with this, global gene-expression analysis confirmed that the 3 fusion oncogenes induced similar transcriptional responses with activation of genes involved in the JAK-STAT pathway.…”

Effects of Dasatinib on Src Kinase Activity and Downstream Intracellular Signaling in Primitive Chronic Myelogenous Leukemia Hematopoietic Cells

“…However, Imatinib resulted in similar suppression of P-STAT, P-Akt, and P-MAPK, suggesting that combined inhibition of Src and Bcr-Abl kinase activity did not result in increased suppression of these signaling pathways. Although GF signaling from autocrine mechanisms has been observed in primitive CML cells even in the absence of exogenous GF (29), autocrine GF production and signaling is Bcr-Abl kinase dependent and rapidly inhibited with Imatinib treatment (30). On the other hand treatment with Dasatinib in the presence of GF did not inhibit P-STAT5 or P-Akt expression in CML CD34 + cells.…”