The role of alternative splicing patterns of BCR/ABL transcripts in the generation of the blast crisis of chronic myeloid leukaemia

Abstract

Three major types of mRNA can be expressed as a result of the Philadelphia translocation, dependent on the position of the break within the BCR gene on chromosome 22. In addition, alternative splicing of the mRNA transcribed from the BCR/ABL fusion gene has been reported and it has been suggested that this may play a role in the generation of the acute phase of Philadelphia positive chronic myeloid leukaemia (CML). We have examined the fusion RNA present in 24 cases of chronic phase CML and 21 cases of patients with CML in blast crisis using the polymerase chain reaction. In no case was it possible to detect the presence of the e1a2 junction which encodes the p190 hybrid protein product. We conclude that the acquisition of the p190 does not play a significant role in the generation of the blast crisis of CML. Neither could we detect a significant difference in the number of cases which simultaneously express both b2a2 and b3a2 junction products in samples isolated from chronic phase and blast crisis. In the series analysed by ethidium bromide stained gels, there was, however, an increase in the percentage of cases expressing the b3a2 junction in the mononuclear cells of blast crisis patients as compared to the white blood cells of patients in chronic phase.

Increased expression of the differentiation-defective granulocyte colony-stimulating factor receptor mRNA isoform in acute myelogenous leukemia

“…Truncated mutant G-CSFR alleles have been identified in, at most, 29% of Kostmann's syndrome patients, and less than 3% of AML patients thus far reported. 35,41,42 The results presented here demonstrate increased relative levels of the naturally occurring class IV isoform in three of seven AML patients, suggesting that this abnormality may be a much more common event in AML.…”

“…41 Point mutations in one allele of the G-CSFR gene in each patient resulted in premature stop codons in the G-CSFR mRNA transcript. The resultant truncations produce mutant receptor isoforms which lack the distal 83 or 97 amino acids of the class I isoform which are required for maturational signaling; the same amino acids which the class IV isoform replaces with novel carboxy-terminal peptide sequence.…”

Analysis of mRNA transcripts in chronic myeloid leukemia patients

“…Only studies in which the type of mRNA was determined by tests with a sensitivity similar to that employed in the present study, i.e., two consecutive rounds of PCR or one round with the use of radioactive probes to detect the amplified fragments, were considered. Data from the following reports were used in our search for associations between mRNA type and clinical parameters: Yin et al (1995) and Shepherd et al (1995) for the Sokal index, 123 cases; Yin et al (1995) and Gaiger et al (1995), for age at diagnosis, 35 cases; Ponzetto et al (1990), Nakamura et al (1991), Shepherd et al (1995), Gaiger et al (1995), Yin et al (1995), and Tanaka et al (1996), for sex, 181 cases; Hooberman et al (1989), Morgan et al (1990), Ponzetto et al (1990), Nakamura et al(1991), Fioretos et al (1993) and Tanaka et al (1996) for cell lineage, 43 cases.…”

Relationship Between the Type of BCR-ABL Rearrangement and Bone Marrow Histopathological Features in Chronic Myeloid Leukemia

“…Its importance in the chronic phase duration, median survival and its correlation with clinical features has been previously described, but the conclusions are still conflicting (7)(8)(9)(10)(11)(12). Considering that megakaryocytic proliferation and fibrosis might be related to the acceleration of CML and unfavourable prognosis (17) and a possible involvement of exon b' in thrombopoietic activity (18,19) we attempted to correlate bone marrow histology with the type of BCR-ABL transcripts.…”