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Chemokines in CML
Chronic myeloid leukemia (CML) are associated with the translocation between
chromosomes 9 and 22, which results in the BCR-ABL fusion protein with
a constitutively active tyrosine kinase activity.
At the initiation phase of CML. a small number of leukemia initiating cells
(ILCs) co-exist with a large number of normal hematopoietic stem/ progenitor
cells (HSPCs) in the bone marrow, and eventually expand to occupy the whole
bone marrow.
In order to induce CML model in mouse, BCR-ABL-expressing LICs are usually
intravenously administered to lethally irradiated mice, with complete abrogation
of normal HSPCs. However, this mouse model lacked completely normal HSPCs
and did not recapitulate the initiation phase of CML.
In order to recapitulate the interaction between ILCs and HSPCs in the
initiation phase of CML, we administered BCR-ABL-epxressing ILCs directly
into non-irradiated nude mice. The mice developed CML-like pathology as
evidenced by a marked leukocytosis and splenomegaly,. Using this mouse
moder, we demonstrated that leukemia cells produced abundantaly a chemokine,
CCL3. We further revealed that the produced CCL3 expeled normal HSPCs from
bone marrow to make free spaces for leukemia cells to grow (Baba et al., 2013).
We subsequently revealed that CCL3 is constituttively expressed by basophils
in normal bone marrow and can inhibit exaggerated proliferation of normal
HSPCs under stress conditions such as bone marrow transplantation.
Basophil-like leukemia cells are icreased abundantly in bone marrow and peripheral blood of human CML patients and mouse CML model and are identifed as a major producer of CCL3. In murine CML model, depletion of basophils can prevent CML development similarly as CCL3 depletion does. Collectively, basophil leulemia-derived CCL3 can prevent the growth of normal HSPCs, which compete over bone marrow niche with LICs and as a consequence, can favor the growth of CML LICs (Below Figure) (Baba et al., 2016). Thus, baosphils and/or CCL3 may be a potent target for CML treatment.