22q11.23

ALL,BCR1,CML,D22S11,D22S662,PHL

t(9;22)(q34;q11)/chronic myelogenous leukemia (CML) --> BCR / ABL

All CML have a t(9;22), at least at the molecular level (BCR/ABL); phenotype and stem cell origin: multipotent progenitor: t(9;22) is found in all myeloid and B- lineage progenitors.

The prognosis of CML has changed radically over the last 10 years, due to the development of novel drugs able to target the enhanced tyrosine kinase activity of BCR-ABL. The first of these therapies is Imatinib Mesylate (Gleevec) which has become the first line therapy for all patients with CML (See ABL and CML). In the first cohort trial of patients treated with Imatinib mesylate, the rates of complete cytogenetics responses (CCR) were exceptionally high (82 %) as compared to standard IFN-alpha - ARA-C therapy. At the most recent 6-year update, the overall survival is 90 % and most interestingly, the rates of progression towards more aggressive phases have been found to be progressively decreasing in all patients with major molecular responses (MMR). (For definition of MMR see CML). In IM-resistant or relapsing Ph1+ CML patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.

Anomalies additional to the t(9;22) may be found either at diagnosis or during course of the disease, or at the time of acute transformation; mainly: +der(22), +8, i(17q), +19; +21, -Y, -7, -17,+17; variant translocations: t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, karyotypes with apparently normal chromosomes 9 and 22, may be found.
Deletion of the derivative chromosome 9: Detected at diagnosis (in 10% of patients), probably indiacting a genetic instability phenotype, this finding has been associated to the more aggressive behavior of the disease, a poor prognostic factor potentially reversed by the use of imatinib mesylate.

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t(9;22)(q34;q11)/acute lymphoblastic leukemia (ALL) --> BCR / ABL

Most often CD 10+ B-ALL; frequent CNS involvement.

The prognosis of Ph1+ ALL has changed since the introduction of tyrosine-kinase inhibitor therapies, especially imatinib mesylate which is currently used as a first line therapy associated with either high dose chemotherapy or classical ALL-type induction (steroids+ vincristine) and maintenance. Allogeneic stem cell transplantation is indicated in Ph1+ ALL patients relapsing after Imatinib-based regimens. In IM-resistant or relapsing Ph1+ ALL patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.

The chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: +der(22), -7, del(7q) most often, +8, but not an i(17q), in contrast with CML and AML cases; complex karyotypes, often hyperploid; variants and complex translocations may be found as in CML.

see below. In Both CML and Ph1+ ALL, detection and quantification of p210 BCR-ABL and p190 BCR-ABL have become the cornerstones of monitoring targeted therapies.

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t(9;22)(q34;q11)/acute myeloid leukemia (AML) --> BCR / ABL

AML mostly M1 or M2 AML

High rates of hematologic , cytogenetic and molecular responses have been reported in de novo PH1+ AML, which is a rare entity.

The chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: similar to what is found in CML.

BCR/ABL the crucial event lies on der(22), id est 5 BCR - 3 ABL hybrid gene is the crucial one, while ABL/BCR may or may not be expressed;
Breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5 of 1b or 3 of 1a, but always 5 of exon 2; breakpoint in BCR is either:

1- in a region called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 KDa chimeric protein (P210); this is found in (most cases of) CML, and in half cases of ALL or AML.

2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), -> 7 kb mRNA, resulting in a 190 KDa protein (P190) found in approximately 25% of adult ALL cases.

3- A breakpoint in the exon 19 of BCR (designed as the micro-bcr) with fusion to abl sequences (a2) has been found in neutrophilic CML, with presence of a larger protein (P230).

BCR/ABL P210 comprises the first 902 or 927 amino acids from N-term of BCR, whereas P190 BCR and P230 include 427 and 1176 aminoacids respectively, from the N-term region of BCR; BCR/ABL has a cytoplasmic localization, probably by the ability of the oligomerization domain to interact with Factin. ABL is both nuclear and cytoplasmic, due to the presence of nuclear localisation and export signals (NLS and NES) within its COOH terminal region.

All three forms of BCR-ABL oncogenes have transforming potential and it is now clear that they are responsible for initiation of the leukemic process associated with BCR-ABL oncogenes: Several signalling pathways are simultaneously activated and some phenotypic correlations can be made with the molecular abnormalities

1- Constitutive activation of RAS pathway (via TYR177 of the BCR) mimicking the growth-factor-stimulation of cells, leads to a proliferative behavior;

2- Activation of PI-3K/Akt as well as JAK/STAT pathways is most likely responsible for the anti-apoptotic potential;

3- BCR/ABL provokes cell adhesive abnormalities (via CRK-L, FAK) as well as abnormalities of cell migration (via CXCR-4 whose expression is downregulated in CML cells expressing high levels of BCR-ABL). In experimental settings CD44 has been shown to play a major role in homing of BCR-ABL expressing cells. Activation of focal adhesion molecules (FAK / ) via CRK-L as well as abnormal response to SDF-1 leads to adhesive and migratory abnormalities of leukemic cells. It should be noted that specific signalling events leading to ALL with P190 and to CML with P210 have not been clearly established. A differential activation of Rho protein could play a role between the two phenotypes: rho Rac and cdc42 interact with BCR-ABL p210 but BCR-ABL p190 activates rac and cdc42 only. Deletion of Ikaros, has recently been implicated as a major oncogenic event cooperating with BCR-ABL in the BCR-ABL+ ALL.

Progression to blast crisis in CML: Multiple events could be involved, with the major phenotype being a genetic instability: 1-Mutation of P53, 2-methylation of internal ABL promoter; 3- telomere shortening; 4- Inhibition of negative regulators of BCR-ABL (such as Abi-1) 5- BCR-ABL induces a major genetic instability: Molecular pathways involved in this phenomenon have recently been elucidated (See ABL AND CML).