Unexpected heterogeneity of BCR-ABL fusion mRNA detected by polymerase chain reaction in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Abstract

The Philadelphia (Ph1) chromosome results in a fusion of portions of the BCR gene from chromosome 22 and the ABL gene from chromosome 9, producing a chimeric BCR-ABL mRNA and protein. In lymphoblastic leukemias, there are two molecular subtypes of the Ph1 chromosome, one with a rearrangement of the breakpoint cluster region (bcr) of the BCR gene, producing the same 8.5-kilobase BCR-ABL fusion mRNA seen in chronic myelogenous leukemia (CML), and the other, without a bcr rearrangement, producing a 7.0-kilobase BCR-ABL fusion mRNA that is seen only in acute lymphoblastic leukemia (ALL). We studied the molecular subtype of the Ph1 chromosome in 11 cases of Ph1-positive ALL, including 2 with a previous diagnosis of CML, using a sensitive method to analyze the mRNA species based on the polymerase chain reaction (PCR). We observed unexpected heterogeneity in BCR-ABL mRNA in this population; in particular, 1 of 6 bcr-rearranged cases and 1 of 5 bcr-unrearranged cases contained none of the known fusion mRNA species, while 1 of the bcr-rearranged cases contained both. This latter case is particularly interesting because it suggests that the acquisition of an additional BCR-ABL fusion species may be a mechanism of disease progression. We conclude that the PCR gives additional information about the Ph1 chromosome gene products that cannot be obtained by genomic analysis, but that it cannot be used as the sole means of detection of this chromosomal abnormality in ALL because of the high incidence of false negative results.

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.…”

Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi)

“…The translocation fuses two unrelated genes, BCR from chromosome 22 and ABL from chromosome 9, to form an oncogenic hybrid gene. With regard to the BCR gene, there are two breakpoint sites, M-BCR versus m-BCR, and hence two slightly different BCR/ ABL oncoproteins of 210 kD or 190 kD, respectively, are produced (Chan et al, 1987;Rubin et al, 1988;Hooberman et al, 1989). The resulting BCR/ABL protein has, as compared to the normal ABL protein, an increased kinase activity leading to pathological phosphorylation of several downstream targets (Lugo et al, 1990;Goldman and Druker, 2001a).…”

Acute Leukemias Expressing p210-and p190-Type <i>bcr/ ab</i><i>l</i> mRNAs: Report of Two Cases and Review of the Literature

“…The simultaneous expression of p210-and pl90-typc bcr/abl mRNAs in Ph'-positive leukemic cells is thought to be rare [9][10][11][12], As summarized in table 2, the clinical features of these reported patients are heterogeneous: 5 with ALL, and at least 2 with CML blast crisis. Only 2 out of 8 patients had a long survival period.…”