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Multiprobe CLL Panel

Applications
haematology, multiprobe
Catalogue Numbers
PMP 018 (2 devices)
PMP 017 (5 devices)
PMP 016 (10 devices)
PMP 020 (20 devices)
MYB Deletion

MYB Deletion

Chromosome 12 Enumeration Probe

Chromosome 12 Enumeration Probe

ATM Deletion

ATM Deletion

IGH/BCL2 Translocation, Dual Fusion

IGH/BCL2 Translocation, Dual Fusion

IGH Breakapart

IGH Breakapart

P53 (TP53) Deletion

P53 (TP53) Deletion

IGH/CCND1 Translocation, Dual Fusion

IGH/CCND1 Translocation, Dual Fusion

13q14.3 Deletion

13q14.3 Deletion

The Chromoprobe Multiprobe® CLL panel has been designed to detect up to eight different FISH probes on a single slide in a single hybridisation experiment. It can be used to determine genotype in leukaemia patients and aid in prognosis and disease management. The panel has been designed to aid in detection of chromosomal aberrations, thereby providing critical information for diagnosis and prognosis.

The orientation of the probes on the panel is illustrated above. More detailed information on the probes can be found below.

Area of Interest*
CLL
  • MYB Deletion

    MYB Deletion

    Deletions of chromosome 6q a re found in B-CLL, with breakpoints being reported in bands 6q13, q15 and q21.

    The MYB gene (Avian Myeloblastosis Viral Oncogene Homolog) is a homologue of the avian v-myb oncogene and has been shown to be highly expressed in all immature lymphoid and myeloid T-cells, but becomes down regulated in mature T or B-cells1. The MYB gene is located in band 6q23.3 and is provided as a marker for 6q deletion as it is distal to reported deletion breakpoints (6q13, 6q15 and 6q21).

    References

    1. Oh and Reddy. Oncogene. 1999 May 13;18 (19):3017-33

  • Chromosome 12 Enumeration Probe

    Chromosome 12 Enumeration Probe

    The chromosome 12 probe on the CLL Panel is a repeat sequence probe, labeled in red, which recognises the centromeric repeat sequence D12Z3. This probe will allow detection of trisomy 12, a recurrent abnormality in CLL.

  • ATM Deletion

    ATM Deletion

    The protein kinase ATM (Ataxia-Telangiectasia Mutated) gene, located in 11q22.3, is frequently deleted in cases of B-CLL. ATM is an important checkpoint gene involved in the management of cell damage and its function is to assess the level of DNA damage in the cell and attempt repair by phosphorylating key substrates involved in the DNA damage response pathway.

    The ATM/P53 (also known as TP53) interaction in B-CLL has been shown to play an important role in the proliferation of lymphoid cancer1. It has been shown that ATM enhances the phosphorylation of P532, should the damage be so great that the cell requires destruction by apoptosis (which is mediated by P53). Deletion of ATM removes this checkpoint activity and hence activation of P53. Thus, there is no attempt made to repair, or apoptosis of, damaged cells, despite the presence of P53. In the absence of ATM, damaged cells are allowed to continue to proliferate.

    Screening for deletions of ATM and/or P53 is vital to allow informed therapy choices for CLL patients, especially as deletions of P53 and ATM confer poor prognosis3.

    References

    1. Stankovic et al., Blood 2004;103(1):291-300

    2. Khanna et al., Nature Genetics 1998;20(4):398-400

    3. Zent et al., Blood 2010;115(21):4154-4155

  • IGH/BCL2 Translocation, Dual Fusion

    IGH/BCL2 Translocation, Dual Fusion

    This is a recurrent rearrangement of IGH in CLL1 and is cytogenetically indistinguishable from the t(14;18) translocation observed in follicular lymphoma.

    The translocation (t(14;18)(q32.33;q21.33)) is thought to be brought about by an error in the joining function of the IGH gene, mediated by the observation that both IGH and BCL2 are arranged next to each other in 3D space in normal B lymphocytes2. The translocation breakpoint at the end of the Joining (J) segment, and the subsequent fusion of the BCL2 gene to this region, results in the BCL2 gene coming under the regulatory control of those processes normally involved in maintenance of IGH gene activity. The protein encoded by the BCL2 gene has been shown to be involved in the regulation of apoptosis.

    References

    1. Bernicot et al., Cytogenet Genome Res. 2007;118(2-4):345-52

    2. Roix et al., Nature Genetics 2003;34(3):287-91

    3. Stoos-Veić et al., Coll Antropol. 2010 Jun;34(2):425-9

    4. Sharpe et al., Biochim Biophys Acta. 20041644(2-3):107-13

  • IGH Breakapart

    IGH Breakapart

    In Burkitt's Lymphoma, IGH is most notably involved in rearrangements involving the MYC oncogene as a result of the t(8;14)(q24.21;q32.33) translocation1. However, other rearrangements of the IGH gene are also seen in a number of different malignancies, including T-ALL, Chronic Lymphocytic Leukaemia (CLL) and Acute Lymphpblastic Leukaemia (ALL). There are a number of stereotypical translocations involved in each of the diseases and more are being described regularly.

    In T-ALL for example, IGH is observed in the t(14;14)(q11;q32) translocation (or inv(14)(q11q32) rearrangement)2 that is found in T-cell leukaemia associated with ataxia-telangiectasia (AT). However, rare reports have indicated that this abnormality also occurs in B-ALL. The recurrent t(14;19)(q32;q13) translocation associated with chronic B-cell lymphoproliferative disorders, such as atypical CLL, has also been shown to occur in B-ALL and results in the juxtaposition of the IGH and BCL3 genes and subsequent over expression of BCL33. More recently, a report suggested the involvement of IGH in a novel cryptic translocation in paediatric T-ALL, which also involved TLX3 (HOX11L2) or NKX2-5 (CSX) on 5q35 brought about by a t(5;14)(q35;q32) translocation4.IGH is involved in a large number of different rearrangements with fusion partners on almost every other chromosome. Many of these rearrangements have been reported in only one or a few cases but some are more common, such as IGH/BCL2, caused by the t(14;18) translocation5, and IGH/CCND1, a result of the t(11;14) translocation6. All these rearrangements do, however, have breakpoints within the IGH gene. We have designed a split probe set for IGH, which allows the detection of rearrangements, regardless of the partner gene involved.

    References

    1. Hoffman, Ronald (2009). Hematology : basic principles and practice (5th ed. ed.). Philadelphia, PA: Churchill Livingstone/Elsevier. pp. 1304-1305

    2. Liu et al., Cancer Genet Cytogenet 2004;152:141-5

    3. Robinson et al., Genes Chromosomes Cancer 2004;39(1):88-92

    4. van Zutven et al., Haematologica 2004;89(6):671-8

    5. Huret JL . t(14;18)(q32;q21) (IgH/BCL2); t(2;18)(p11;q21); t(18;22)(q21;q11). Atlas Genet Cytogenet Oncol Haematol. 
May 1998

    6. Huret JL . t(11;14)(q13;q32). Atlas Genet Cytogenet Oncol Haematol. May 1998

  • P53 (TP53) Deletion

    P53 (TP53) Deletion

    Although previously difficult to detect, the advent of FISH analysis of interphase cells from patients with B-CLL showed that around 17% of patients with the disease have deletions of the P53 (TP53) gene1. As with ATM, deletions of P53 have important therapeutic implications for patients with B-CLL2.

    Knowledge of the P53 deletion status in the patient should mediate the choice of therapy3. P53 is a tumour suppressor gene and its protein product is responsible for the death of cells that contain damaged DNA. This is thought to be brought about by phosphorylation of P53 and the subsequent prevention of its repression by MDM2 (Mouse Double Minute 2 Homolog). This phosphorylation is mediated by ATM. In the absence of P53 activity, cells that cannot be repaired by ATM will continue to proliferate in their damaged state. Patients deleted for P53 may be rendered resistant to alkylating chemotherapeutic agents3 and purine analogues4 as these are designed to damage DNA in the cells that P53 would have destroyed. In the absence of P53, therefore, patients treated with these agents will harbour a proliferating population of damaged cells.

    References

    1. Döhner et al., J Mol Med 1999;77:266-81

    2. Foá et al., Haematol 2013; 98(5):675-685

    3. Sturm et al., Cell Death Differ. 2003 Apr;10(4):477-84

    4. Döhner et al., Blood. 1995 Mar 15;85(6):1580-9

  • IGH/CCND1 Translocation, Dual Fusion

    IGH/CCND1 Translocation, Dual Fusion

    Although translocations involving IGH and CCND1 (BCL1) were initially reported in B-CLL patients, the rearrangement is now considered to be a hallmark of mantle cell lymphoma (MCL).

    Reciprocal translocations involving the IGH and CCND1 (previously known as BCL1) loci, t(11;14)(q13;q32), have been reported in B-CLL patients1. The involvement of the CCND1 (Cyclin D1) gene was initially reported from a cloning study looking at the breakpoints of the translocation. However, it is likely that the initial diagnosis on the samples used for the study should have been mantle cell lymphoma (MCL). The CCND1/IGH probe for detection of t(11;14) has been recommended by the British Committee for Standards in Haematology to enable atypical B-CLL patients to be distinguished from possible MCL patients2.

    References

    1. Brizard et al., Leuk Lymphoma 1997;25(5-6):539-43

    2. Parker et al., Best Practice in Lymphoma Diagnosis and Reporting; Specific disease appendix 2010, p5

  • 13q14.3 Deletion

    13q14.3 Deletion

    Chromosome 13q abnormalities occur in 16-40% of multiple myeloma cases and are associated with poor prognosis1,2.A case study has shown that in 90% of patients, the 13q14 region was affected and 68% also showed involvement of the 13q21 region – the critical region in all but 8 patients was narrowed down to 13q143. Deletions affecting 13q14 are also the most frequent structural genetic abnormalities in B-cell Chronic Lymphocytic Leukaemia (B-CLL)4. This region is found to be heterozygously deleted in 30-60% and homozygously deleted in 10-20% of CLL patients5. Recently though, the survival rate has been shown to be similar for the two groups6.Two non-coding RNA genes, DLEU1 and DLEU2, and the genetic marker D13S319, span the pathogenic critical region of 13q147. DLEU1 is considered to be the most likely CLL-associated candidate tumour suppressor gene within the 13q14 region8. Subsequently, D13S319, located between the RB1 gene and D13S25 and within the DLEU1 locus, was found to be deleted in 44% of CLL cases9. It has also been postulated that a gene telomeric to the D13S319 region, encompassing D13S25, may be important in cases with hemizygous deletions and that this gene is a putative tumour suppressor gene10.

    References

    1. Bullrich F et al., Cancer Res 2001;61:6640-8

    2. Zojer et al., Blood 2000;95(6 ):1925-1930

    3. Shaughnessy J et al., Blood 2000;96:1505-11

    4. Juliusson G et al., N Eng J Med 1990;323:720-4

    5. Hammarsund M et al., FEBS Letters 2004;556:75-80

    6. Van Dyke DL et al., Br J Haematology 2009;148:544-50

    7. Liu Y et al., Oncogene 1997;15:2463-73

    8. Wolf S et al., Hum Mol Genet 2001;10:1275-85

    9. Liu Y et al., Blood 1995;86:1911-5

    10. Bullrich F et al., Blood 1996;88(8):3109-15

Disclaimer

This product is intended to be used on Carnoy’s solution (3:1 methanol/acetic acid) fixed haematological samples.

*Disease information supported by the literature and is not a reflection of the intended purpose of this product.