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Chapter 11 Hematopoietic Microenvironment 125

Other molecular mediators of LSC–microenvironment interac- questions remain. We still know very little about the molecular
tion have also been identified. B4 integrin (also known as very late mediators of “niche-induced oncogenesis” and those involved in
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antigen 4). mediates lodgment of leukemic cells in the BM and microenvironment-induced chemoresistance. Recent advances in
interacts with fibronectin to confer resistance to cytosine arabinoside- xenotransplantation assay using highly immunocompromised mouse
induced apoptosis. Integrin ligation triggers prosurvival pathways, strains for the study of normal and leukemic hematopoiesis, together
and the blocking antibody leads to reduction in the level of leukemic with further molecular insights into biology of leukemic stem cells,
burden and a modest prolongation of the lifespan in human AML- will provide an opportunity to address these issues.
transplanted animals. Similar protective role for AML blasts has been Therapeutic manipulation of the hematopoietic microenviron-
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observed for β1 and β2 integrins. IL-3 receptor α chain (CD123). ment remains an ultimate goal of ongoing research. Clearly, the effort
also contributes to LSC survival, at least partly through being involved of the next several years will be focused on translating the wealth of
in controlling LSC homing to the BM; CD123 blocking antibody data obtained from the animal models into human biology and the
demonstrated considerable antileukemic activity, which was also clinic. This work has already started with the clinical trials of ex vivo
attributable to promoting immune-mediated destruction of leukemic HSPC expansion before cord blood transplantation. A number of
cells. This idea that has been explored further in the studies of clinical trials are also underway to examine the efficacy of niche-
blocking a macrophage-associated molecule CD47. Expression of directed therapies in hematologic malignancies. Although the animal
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CD47 on LSCs appears to protect the LSCs from phagocytosis. data suggest that targeting the niche alone is often insufficient to
CD47 expression is associated with Flt3-ITD mutation and indepen- achieve cure, especially in an established disease, this approach has
dently predicts worse prognosis. Mechanistically, CD47 acts as a “do been successful in regaining leukemia chemosensitivity to commonly
not eat me” signal for the macrophages. Blocking CD47 antibody used agents and may become a valuable component of future treat-
produces depletion of AML in xenotransplantation models and ment protocols, particularly in the setting of low tumor burden, such
specific eradication of LSCs. Phase 1 study of CD47 antibody in as minimal residual disease. Gaining a deeper insight into the molecu-
hematologic malignancies and solid tumors is ongoing. lar distinctions between normal and malignant niches will enable
Emerging experimental evidence (using the chemical marker of better understanding of “niche competition” between normal and
hypoxia pimonidazole) suggests that leukemic BM niches are hypoxic leukemic populations and lead to development of novel approaches
and that leukemic cells adapt to hypoxic conditions. Although low based on eradication of leukemic cells and fostering normal hemato-
oxygen tension within the leukemic niche remains to be directly poiesis through manipulation of niche-derived signals.
demonstrated, the findings of overexpression of the key hypoxia-
response factor HIF1-α in clusters of ALL cells, together with
increased angiogenesis and production of VEGF by the ALL blasts REFERENCES
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