STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients

Abstract

A signal transduction pathway activated by many cytokines has recently been elaborated. The JAK kinases and the signal transducers and activators of transcription (STAT) factors have been found to be essential components. In this report, we describe the presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia. We used oligonucleotide probes from the beta-casein and IRF-1 gene promoters and the ISRE probe to detect STAT proteins in nuclear extracts from acute leukemia cells in bandshift assays. Specific DNA protein complex formation was observed with the probes from the beta-casein and IRF-1 gene promoters, but not with the ISRE oligonucleotide probe, when cell extracts from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were investigated. We used nonradioactive oligonucleotides as competitors to show the specificity of the complex formation. Specific antibodies directed against the individual STAT proteins were used in supershift experiments. STAT5- and STAT1-related factors were detected in ALL and STAT1-, STAT3-, and STAT5-related proteins were present in nuclear cell extracts from AML. Since the cells were not treated with cytokines before the nuclear proteins were extracted, we conclude that these factors are constitutively activated in vivo. It is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis.

Constitutive activation of STAT transcription factors in acute myelogenous leukemia

“…Owing to continuous passage, acquisition of multiple genetic aberrations, selection etc., primary AML blasts and AML cell lines might differ significantly in their biological and genetic characteristics. However, a constitutive activation of STAT proteins has been described in primary AML blasts (9, 11), which shows that this observation is not an artefact of continuous cultivation or selection. In primary AML blasts a constitutive activation of STAT3 and 5, but not STAT2, 4 or 6, has consistently been observed by others.…”

“…acute and chronic myeloid and lymphocytic leukemias (8). In primary AML blasts STAT3 and 5, but not STAT2, 4 or 6, are constitutively bound to DNA (9, 10). However, the frequency of STAT activation found in AML differs significantly in reports from different groups and ranges from 20 to 80% (10, 11).…”

STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells

“…Screening for activating mutations of STAT5A and 5B in human leukemic patients is now in progress. It will also be of interest to test IL‐3 or IL‐2 for growth inhibitory effects on the leukemic cells showing abnormal STAT activation (Migone et al ., 1995; Gouilleux‐Gruart et al ., 1996; Weber‐Nordt et al ., 1996). Our present study suggested that among a diverse set of genes activated by the mutant STAT5, pim‐1 expression plays a pivotal role in inducing autonomous cell growth.…”

The role of the STAT5 proteins in the proliferation and apoptosis of the CML and AML cells

“…In contrast to CML, multiple chromosomal translocations can be found in AML blasts (10, 36). STAT5 has been reported to be constitutively activated in the AML blasts from peripheral blood of patients and from cell lines from 22% to 94% by various groups (10, 11, 36–38). The molecular cause for constitutive STAT5 activity is still largely unknown.…”

“…interleukin‐3 (IL‐3), granulocyte macrophage‐colony stimulating factor (GM‐CSF), granulocyte‐colony stimulating factor (G‐CSF), erythropoietin (EPO), thrombopoietin (TPO) and kit ligand (KL), which stimulate haematopoietic cell proliferation and development (1, 7). The STAT5 proteins are constitutively activated in some haematological malignancies such as acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL), chronic myeloid leukaemia (CML), HTLV‐I‐related adult T‐cell leukaemia/lymphoma, thereby suggesting their importance in leukaemogenesis (8–11). To date, it is still uncertain which of these two proteins is more responsible for leukaemogenesis.…”