Interferons regulate the in vitro differentiation of multilineage lympho-myeloid stem cells in hairy cell leukemia.

Abstract

In vitro 14-day cultures of peripheral blood mononuclear cells from hairy cell leukemia patients consistently showed the presence of hematopoietic stem cells giving rise to multilineage colonies containing a high proportion of lymphoid cells associated with the myeloid and erythroid progenitors. These stem cells are not the hairy cells but appear to be pluripotent lymphomyeloid primitive stem cells persisting in this leukemia. Interferon ac or .f1 did not inhibit the growth of these colonies, as they did the growth of colonies of normal hematopoietic progenitors, but markedly decreased the ratio of lymphoid to myelomonocytic cells, by increasing the formation of monocytes and other nonlymphoid cell types in these multilineage colonies. Interferon ydid not have the same effects on differentiation.The existence of hematopoietic primitive stem cells giving rise to the lymphoid progeny, as well as to the other blood cell lineages, has been inferred from the genetic study ofleukemia clones in vivo (1), and these rare cells seem to be detectable in a few hematopoietic disorders. Thus, cultures of bone marrow (BM) and peripheral blood mononuclear cells (PBMC) from non-Hodgkin lymphoma and chronic myelogenous leukemia patients may produce multilineage colonies with lymphoid and myeloid cells (2, 3). We have studied hematopoiesis in cells from patients with hairy cell leukemia (HCL), a disease characterized by pancytopenia and, in BM, spleen, and often peripheral blood, by accumulation of incompletely differentiated, preplasmatic B lymphocytes with low proliferation, with typical morphology, and also with the interleukin 2 receptor Tac antigens as well as unexplained monocyte markers (4-6). Long-term interferon (IFN) a injections can reduce the hairy cell mass but, more strikingly, restore the levels of granulocytes, macrophages, platelets, and erythrocytes in HCL patients (7-9).In vitro hematopoietic colony cultures from the peripheral blood of HCL patients consistently had multilineage colonies containing many B lymphocytes associated with the myeloid cells but poor in monocytes. These colony-forming cells are distinct from the hairy cells. Type I human recombinant IFN-a or -,3 profoundly affects the differentiation pattern of the HCL lymphomyeloid stem cell cultures: the formation of myeloid and monocytic elements, as well as the formation of normoblasts and megakaryocytes, is enhanced, whereas the number of lymphoid cells decreases. Type II IFN-y has no such effect. These findings may be related to the mechanism by which type I IFNs induce remission and relieve pancytopenia in HCL patients. HCL provides an experimental model for the study of primitive multilineage lymphomyeloid stem cells growth and differentiation and for the study of the effects of IFN on this process. MATERIALS AND METHODSColony-Forming Cultures for Hematopoietic Progenitors. Cells were cultured essentially as described (3, 10). PBMC were separated from heparinized blood by Ficoll/Hypaque (Pharmacia) centrifugation and washed. Cells that d...

A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.

“…IFNs protect cells against viral infection, regulate cell proliferation and differentiation, and activate immune effector cells such as natural killer cells and macrophages (1). Type I IFNs also may affect hemopoiesis (4)(5)(6): for example, IFN-a/f3 is produced by cultured murine bone marrow (BM) cells in response to colony-stimulating factor 1 (CSF-1) and may suppress or induce differentiation depending on the experimental conditions (6). IFN-a and -13 are constitutively produced by hemopoietic cells (6)(7)(8)(9), but direct evidence of an in vivo role for constitutive IEN in hemopoiesis is lacking.…”

Activation of Different Stat5 Isoforms Contributes to Cell-Type-Restricted Signaling in Response to Interferons

“…Moreover, they affect the proliferation and differentiation of hematopoietic cells. Secretion of type I IFN occurs upon stimulation of myeloid progenitors with differentiating stimuli and was suggested to be essential for the generation of phenotypically correct mature hematopoietic cells both in vitro (43,54) and in vivo (29). IFN-␥ on its own was shown to induce surface markers characteristic for differentiated cells on myeloid progenitors but to require cooperation with a second differentiating stimulus to produce all phenotypes and functional attributes of a mature cell (47,65,66).…”

Expression of the IFNα receptor in hairy cell leukaemia

“…IFNa2 in hairy cell leukaemia include induction of expression of class I1 human lymphocyte antigens (HLA) on hairy cells (Baldini et al, 1986: Gressler et al, 1988, and a direct effect on multilineage lympho-myeloid stem cells derived from the bone marrows of these patients (Michalevicz & Revel, 1987). He had a relapse in November of 1985, and was retreated with IFNrZ obtaining again a partial remission, The studies were performed at a subsequent relapse in January of 1991.…”

“…The patient died in May 1990, after a presumed cardiovascular incident. IFNa2 in hairy cell leukaemia include induction of expression of class I1 human lymphocyte antigens (HLA) on hairy cells (Baldini et al, 1986: Gressler et al, 1988, and a direct effect on multilineage lympho-myeloid stem cells derived from the bone marrows of these patients (Michalevicz & Revel, 1987). Cordingley et al(1988) also showed that one of the mechanisms of interferon action may be the inhibition of autocrine tumour necrosis factor (TNF)-induced hairy cell proliferation.…”