This case seems to represent an exceedingly rare instance of Ph1(+),i(17q) ALL in which the differential diagnosis between blast transformation of CML and Ph1(+) ALL was initially difficult to make.
Rearrangements in the BCR gene first intron, the so-called bcr2 and bcr3 regions, were detected in two other cases, one with an acute lymphoblastic leukemia (ALL) and one with mixed acute leukemia.
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).
A series of five single-copy genomic probes from the 70-kilobase first intron of BCR were used to localize rearrangements in 8 of 10 Philadelphia chromosome-positive ALLs.
Within the group of Ph'-positive ALL patients having a bcr gene breakpoint, a correlation appears to exist between the age of the patient and the location of the breakpoint within the gene: all or the vast majority of pediatric patients analyzed to date do not have a Mbcr breakpoint as found in CML and in adult ALL.
In CML the translocation breakpoint on chromosome 22 is within the breakpoint cluster region, while in childhood ALL, no detectable change in breakpoint cluster region is routinely observed.
Philadelphia (Ph1) chromosome breakpoints in acute lymphoblastic leukemia (ALL) are of two kinds: those within the breakpoint cluster region (bcr+), as in chronic myeloid leukemia (CML), and those outside it (bcr-).
Twenty patients had chronic myeloid leukemia in blast crisis (CML-BC), three had Ph+ de novo acute nonlymphocytic leukemia (ANLL), and five had de novo acute lymphoblastic leukemia (ALL).
Homozygous deletions of p16 exons were found in 5 of 10 (50%) patients with CML in lymphoid BC and in 5 (26%) ALL patients, but in only 1 (2%) case with AML.
95% of Chronic Myelocytic (CML) and 15-25% of Acute Lymphoblastic Leukemia (ALL) patients are Ph1 producing a fusion transcript between the abl proto-oncogene and the bcr gene.
Both retained the Ph1 chromosome and expressed the ALL type bcr/abl chimeric mRNA containing the junction of the first exon of BCR gene (e1) and second exon of c-abl gene (a2).
We have now used the same technique, reverse transcription/polymerase chain reaction amplification of ABL-BCR transcripts, to study nine patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL); seven expressed the P190 and two the P210 type of BCR-ABL fusion protein.
In the present study, we analyzed blood or bone marrow smears of 46 patients (34 with chronic myeloid leukemia [CML] and 12 with acute lymphoblastic leukemia [ALL]) for the presence of a BCR-ABL fusion.
Southern blot analysis revealed no rearrangement in Mbcr1, and direct sequencing of the PCR product confirmed it to be the ALL-type mbcr1 fusion mRNA with the first exon of the BCR gene fused to ABL exon a2.
Among hematopoietic malignancies, the highest frequencies of p15del and p16del were seen in acute lymphoblastic leukemia (ALL) (>30%) with striking rates in T-ALL (>50%), but also high rates in B cell precursor (BCP)-ALL (>20%); the rates of deletions in chronic lymphoid leukemia (CLL), multiple myeloma, acute and chronic myeloid leukemia (AML and CML), and myelodysplastic syndromes (MDS) were rather low, only some B cell and T cell lymphomas showed increased frequencies.
The ABL gene on chromosome band 9q34 is a proto-oncogene and is the well-known translocation partner of the BCR gene on 22q11 giving rise to t(9;22)(q34;q11), which is the hallmark of chronic myeloid leukemia and is the most common chromosomal abnormality in adult acute lymphoblastic leukemia (ALL).
The Japan Adult Leukemia Study Group (JALSG) has recently started a phase 2 trial with intensive chemotherapy and imatinib for newly diagnosed BCR-AB-positive ALL patients, and we present here the interim results for the first 24 patients.
In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.
Detectable by fluorescence in situ hybridization (FISH), these losses of sequence include deletion of the 5' region of the ABL gene and the 3' region of BCR in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), as well as the 5' region of ETO in acute myeloid leukemia (AML) French-American-British type M2 associated with t(8;21), 3'MLL in AML and ALL, and 3' core-binding factor beta (CBFbeta) in AML associated with inv(16).
The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis.