bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice.

Abstract

The chromosome translocation forming the hybrid bcr‐abl gene is thought to be the initiating event in chronic myeloid leukaemia (CML) and some cases of acute lymphoblastic leukaemia. To assess the impact of bcr‐abl upon haemopoiesis, lethally irradiated mice were reconstituted with bone marrow cells enriched for cycling stem cells and infected with a bcr‐abl bearing retrovirus. The mice developed several fatal diseases with abnormal accumulations of macrophage, erythroid, mast and lymphoid cells, and marked strain differences in disease distribution and kinetics. Some mice exhibited more than one neoplastic cell type and, in some instances, these were clonally related, indicating that a progenitor or stem cell had been transformed. While classical CML was not observed, the macrophage tumours were accompanied by a mild CML‐like syndrome, probably due to myeloid growth factor production by tumour cells. The erythroid and mast cell diseases were rarely transplantable, in contrast to the macrophage tumours and lymphomas, but all disease types displayed limited clonality. These results establish that bcr‐abl confers a proliferative advantage on diverse haemopoietic cells but complete transformation probably involves additional genetic changes.

Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein

“…However, two other groups reconstituted mice with the same method but those mice and a bcr-abl transgenic line developed acute lymphocytic leukemia (Elefanty et al, 1990;Heisterkamp et al, 1990;Kelliher et al, 1990). Further re®nement of the mouse model appears to be required to develop in vivo assays for the pathogenic e ects of Bcr-Abl.…”

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…1928) and David Hungerford ) discovered the Philadelphia chromosome, 9 which was later shown to harbor an oncogenic BCR-ABL1 fusion transcript, which is the disease-causing mutation in chronic myelogenous leukemia. [10][11][12][13][14] Accordingly, PMF is currently grouped with PV and ET as BCR-ABL1-negative MPN. 15 In addition to the previously mentioned JAK2V617F, 7 PMF and the other BCR-ABL1-negative MPNs are characterized by many other somatic mutations, including MPL, TET2, ASXL1, CBL, IDH1, IDH2, IKZF1, LNK, EZH2, DNMT3A, CUX1, and SF3B1 mutations.…”

Models of chronic myeloid leukemia

“…The myeloid cells express Bcr/Abl protein, contain increased levels of tyrosine phosphorylated proteins, and carry the retroviral provirus in chromosomal DNA, confirming that the disease was directly induced by BCR/ ABL. In addition to the CML-like disease, other recipients developed distinct hematopoietic malignancies, including B-lymphoid leukemia (similar to that observed in BCR/ABL transgenic mice), tumors of monocyte-macrophage lineage, and occasionally erythroleukemia and T-lymphoid leukemia [1,2,31]. The CML-like disease could be transferred to secondary recipients by transplantation of marrow, but with low efficiency [32,33].…”

“…Interestingly, only a small subset of the clones present in the primary mice contributed to day-12 spleen colonies [36•] and induced disease in secondary recipients [35•,36•], suggesting heterogeneity between individual clones contributing to the expansion of myeloid cells in the primary animal, with only a minor subset capable of self-renewal as assessed by secondary transplantation. Did not observe CML-like disease in C57Bl/6 and DBA mouse strains [31] p210 CML, mast-cell disease, B/T-ALL Secondary transplantation of CML-like disease and clonally related acute myeloid and lymphoid leukemias [32] p190, p210 CML, B-ALL, macrophage disease p190 induced leukemias of shorter latency than p210 [48] p210 CML, B-ALL, macrophage disease, EL BCR/ABL-induced leukemias influenced by mouse strain and transduction conditions [37] p210 CML, B/T-ALL, macrophage disease…”