Granulopoiesis in long‐term culture by marrow from mice with busulfan‐induced chronic latent aplasia

Abstract

Mice given high-dose busulfan therapy develop a chronic latent marrow aplasia characterized by normal peripheral blood neutrophil numbers, hematocrits and marrow cellularity but reduced numbers of pluripotent hemopoietic stem cells (CFU-s) and granulocyte-monocyte progenitor cells (CFU-gm). To study the pathogenesis of this lesion, bone marrow was propagated in long-term marrow cultures (LTMC). Small amounts of normal marrow readily established and sustained long-term granulopoiesis in vitro. In contrast, inocula of marrow from busulfan-treated animals containing three to five times as many stem and progenitor cells failed to establish long-term granulopoiesis in vitro. These results suggest that high-dose busulfan therapy produces a qualitative defect in either the hemopoietic stem cells, the stromal-forming elements, or both, rendering them incapable of establishing long-term granulopoiesis in vitro. Furthermore, mixing experiments employing normal and busulfan-damaged marrow demonstrate that this qualitative defect is not due to the emergence of a suppressor cell population. LTMC can show types of marrow damage not detectable by other techniques currently available and represent a powerful tool for studying latent bone marrow failure.

Haemotoxicity of busulphan, doxorubicin, cisplatin and cyclophosphamide in the female BALB/c mouse using a brief regimen of drug administration

“…The current changes (Table 2) also generally compare with other reports in the mouse (Boggs and Boggs 1980;Fitchen and Cline 1980;Jelkmann and Bauer 1980;Ideriha et al 1984;McManus and Weiss 1984;Boyd et al 1986;Kato et al 1988), the rat (Elson 1955;Elson et al 1958;Dunn and Elson 1970;Santos and Tutschka 1974), the rabbit (Den Ottolander et al 1982) and rhesus monkey (Kang et al 2006).…”

Animal Models for Acquired Bone Marrow Failure Syndromes

“…19,20 In another study, busulfan therapy resulted in a chronic latent marrow aplasia characterized by normal peripheral blood neutrophil numbers, normal hematocrit and marrow cellularity, but reduced numbers of pluripotent hematopoietic stem cells and CFU-granulocyte-macrophage (CFU-GM). 21 Inocula from busulfan-treated animals containing three to five times the stem cells and progenitor cells failed to establish long-term granulopoiesis in vitro, while small numbers of normal BM cells readily established and sustained long-term granulopoiesis in vitro. These results suggest that busulfan therapy produced a qualitative defect in either the hemopoietic stem cells, the stromal-forming elements, or both.…”

“…These results suggest that busulfan therapy produced a qualitative defect in either the hemopoietic stem cells, the stromal-forming elements, or both. 21 Pugsley et al 22 studied busulfan-induced chronic hypoplastic marrow failure in an experimental murine model and found a 60% to 70% reduction in B lymphocytes and a 30% to 80% reduction in T lymphocytes. There was a two-thirds reduction in IgG and IgM antibody titer to sheep red blood cells and a dramatic decline in lymphocyte proliferative responses in vitro, indicating that the lesions underlying experimental marrow failure are not confined to the myeloid stem cell, but also involve cells of the lymphoid lineage.…”

Different behavior of SCE‐eliciting lesions induced by low and high doses of busulfan

“…Exposure causes failure of proliferation of stem cells and their progeny [Morley et al, 1978;Boyd et al, 1986], involving all progenitor cells [Kubota et al, 1983]. The fact that after busulfan treatment some stem cells survive and subsequently resume hematopoiesis [Jopling and Rosendaal, 2001], and that complete sustained lymphoid reconstitution by transplanted congenic donor stem cells occurs after busulfan administration [Yeager et al, 1991], suggests that the primary action of busulfan is on the stem cells rather than on the microenvironment [Halka et al, 1987].…”