CML mouse model reveals previously unreported facets of disease

By Shreeya Nanda, Senior medwireNews Reporter

A humanised murine model of chronic phase chronic myeloid leukaemia (CML), developed by a Swedish research team, provides insight into previously unexplored characteristics of the disease.

To create this model, the team led by Thoas Fioretos, from Lund University, transplanted human cord blood CD34⁺ cells that retrovirally co-expressed the BCR–ABL1 oncogene and a green fluorescent protein (GFP) marker into immunodeficient mice, lacking interleukin-2-receptor γ.

The majority of the transplanted animals developed signs of disease, including a significant red blood cell count fall, within 100 days of being injected.

BCR–ABL1 expression induced an expansion of human myeloid cells, as assessed by the expression of CD33, in the bone marrow and spleen of transplanted mice. However, increases were noted both in cells positive and negative for GFP, indicating that this expansion was not restricted to cells expressing the oncogene, the researchers report.

Several subtypes of the myeloid lineage, such as erythroid cells (positive for glycophorin A) and macrophages/histiocytes (positive for CD 14 and CD68), were significantly expanded in the bone marrow and spleen of transplanted mice. BCR–ABL1 expression directly and indirectly affects these cell populations, say the authors, as once again GFP-positive and -negative cells were expanded.

By contrast, mast cells, which co-express the markers CD68 and CD117, were significantly expanded in only GFP-positive bone marrow and spleen cells of transplanted animals.

BCR–ABL1 expression also affected cells of the lymphoid lineage, causing a block in the differentiation of B cells at the pre-B-cell stage in transplanted mice. Analysis of mononuclear cells from chronic phase CML patients showed that this B-cell-differentiation block is also a feature of human disease.

Additionally, CD3⁺ human T cells were significantly increased in the spleen of transplanted mice, both in cells expressing and not expressing GFP, but this expansion of T cells was seen only in GFP-negative bone marrow cells.

Fioretos et al note that the expansion of macrophages/histiocytes and T cells is indicative of an inflammatory response.

“This model should hence be valuable for further studies aimed at understanding the disease pathogenesis of CML”, the team concludes in Blood Cancer Journal.

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