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.
BCR-ABL1 signal patterns were analyzed using FISH in 243 CML-chronic phase (CML-CP), 17 CML-blast phase (CML-BP) and 52 BCR-ABL1 positive acute lymphoblastic leukemia (ALL) patients.
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.
Although "paired box 5" (PAX5)-related fusion genes are well documented in childhood B-cell precursor acute lymphoblastic leukemia (ALL), these types of fusion with the exception of PAX5-JAK2 are rarely seen in patients with gene expression profiles similar to those of BCR-ABL1 (Philadelphia)-positive ALL (Ph-like ALL).
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.
At the 60<sup>th</sup> month, estimated CBMR and CEMR incidences were, respectively, 14.3 (5.1)% and 25.9 (6.6)% in ALL, 25.8 (5.9)% and 15.5 (4.8)% in AML, and 61.5 (16.5)% and 17.9 (13.4)% in CML.
Basically two types of BCR-ABL1 chimeric mRNA transcripts have been observed: (1) e13a2/e14a2 transcripts in CML and ALL, resulting from chromosomal breaks in the major breakpoint cluster region (M-bcr) of the BCR gene and (2) e1a2 transcripts in ALL resulting from breaks in the minor breakpoint cluster region (m-bcr) of 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).
CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph<sup>+</sup> ALL exhibiting BCR/ABL1<sub>p210</sub>, whereas in Ph<sup>+</sup> ALL with BCR/ABL1<sub>p190</sub>, LSCs variably expressed CD25 but did not express CD26.
Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) are associated with fusion of the BCR and ABL1 genes by chromosome translocation.
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).
Furthermore, better characterization of the molecular genetic events can drive therapeutic decisions: a historical example in this respect is represented by the use of tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive ALL; in the upcoming future, TKIs might be used also in other subgroups, such as breakpoint cluster region/Abelson 1-like cases and others with deregulated tyrosine kinases.
Fusion genes were detected by F-qRT-PCR in 97.3% of patients with CML, followed by 69.4% with AML, 33.3% with acute lymphoblastic leukemia (ALL), 9.1% with myelodysplastic syndromes (MDS), and 0% with chronic lymphocytic leukemia (CLL).
Genetic alterations of IKZF1 encoding the lymphoid transcription factor IKAROS are a hallmark of high-risk B-progenitor acute lymphoblastic leukemia (ALL), such as BCR-ABL1-positive (Ph+) and Ph-like ALL, and are associated with poor outcome even in the era of contemporary chemotherapy incorporating tyrosine kinase inhibitors.
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.
In 16 samples of normal karyotype ALL (n=9), ALLwith no cytogentic result (n=4) and CML with no Philadelphia chromosome (n=3), fusion transcripts were detected.
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.
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.
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).
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.
In this cohort of Taiwanese children, the relative frequencies of the 4 translocations of B-lineage ALL were 8% with ALL-type t(9;22)/BCR-ABL1, 4% with (1;19)/TCF-PBX1, 2% with t(4;11)/MLL-AF4, and 17.6% with t(12;21)/ETV6-RUNX1.