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Hyperdiploidy associated with T315I mutation in BCR-ABL kinase domain in an accelerated phase-chronic myeloid leukemia case.

Al-Achkar W, Moassass F, Ikhtiar A, Liehr T, Othman MA, Wafa A - Mol Cytogenet (2014)

Bottom Line: A complete cytogenetic and molecular cytogenetic analysis; molecular biology methods such as quantitative reverse transcription polymerase chain reaction (RQ-PCR) and allele-specific oligonucleotide (ASO)-PCR; and immunophenotypically confirmed CML in acceleration phase (AP).The patient demonstrated a good response to nilotinib after imatinib failure; while the hyperdiploid clone disappeared the T315I mutation remained during follow-up.The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.

View Article: PubMed Central - PubMed

Affiliation: Human Genetics Division, Department of Molecular Biology and Biotechnology, Atomic Energy Commission, P.O. Box 6091 Damascus, Syria.

ABSTRACT

Background: Chronic myeloid leukemia (CML) is genetically characterized by the occurrence of a reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22, i.e. the Philadelphia (Ph) chromosome. During CML progression 60-80% of the cases acquire additional genetic changes. Even though hyperdiploidy is not a rare finding in advanced phase-CML, hyperdiploidy together with a T315I kinase domain (KD) mutation in the BCR-ABL gene has not yet been reported.

Results: A complete cytogenetic and molecular cytogenetic analysis; molecular biology methods such as quantitative reverse transcription polymerase chain reaction (RQ-PCR) and allele-specific oligonucleotide (ASO)-PCR; and immunophenotypically confirmed CML in acceleration phase (AP). Our case revealed the presence of hyperdiploidy including multiple copies of the Ph chromosome, presence of b3a2 fusion transcript,T315I mutation in BCR-ABL KD in pre imatinib mesylate (IM) treatment. The ratio of BCR-ABL/ABL expression in post nilotinib treatment was 0.07% on international scale.

Conclusions: The patient demonstrated a good response to nilotinib after imatinib failure; while the hyperdiploid clone disappeared the T315I mutation remained during follow-up. The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.

No MeSH data available.


Related in: MedlinePlus

ASO-PCR monitoring and corresponding sensitivity test for detected T315I mutation Post-nilotinib treatment. Line M, 1 kb DNA ladder; lines 1–8 patients ASO-PCR T315I wild-type primers; P, our patient; lines 9–16 ASO-PCR T315I mutated primers; and P*, our patient with T315I mutation.
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Fig4: ASO-PCR monitoring and corresponding sensitivity test for detected T315I mutation Post-nilotinib treatment. Line M, 1 kb DNA ladder; lines 1–8 patients ASO-PCR T315I wild-type primers; P, our patient; lines 9–16 ASO-PCR T315I mutated primers; and P*, our patient with T315I mutation.

Mentions: Pre IM treatment banding cytogenetics revealed a karyotype of 46,XY,t(9;22)[7]/56,XY,+3,+6,+7,+8,+8,+9,t(9;22),+10,+12,+19,+der(22)t(9;22)[5]/57,XY,+3,+6,+7,+8,+8,+9,t(9;22),+10,+12,+15,-18,+19,+der(22)t(9;22)x2[8]. Post nilotinib treatment banding cytogenetics revealed a karyotype of 46,XY,t(9;22)[1]/46,XY[39] (Figure 1). Further studies were done based on molecular cytogenetics (Figure 2) and molecular genetics (Figure 3). Dual-color-FISH pre IM treatment; using a specific probe for BCR and ABL1 revealed onefusion signal on the derivative chromosomes 9 [der(9)] and another three fusion signals on the up to three Ph chromosomes (Figure 2); and chromosomes 3, 6, 7, 8, 9, 10, 12, 15, 19 and 22, were studied with WCP and/or CEP probes and did not provide any hint on cryptic translocations (data not shown). RT-PCR pre IM treatment and post nilotinib treatment confirmed the presence of the BCR-ABL1 fusion (b3a2 transcript) revealing a major M-BCR transcript (data not shown). RQ-PCR post nilotinib treatment demonstrated a ratio of BCR-ABL/ABL1 expression of 0.07% on IS (data not shown). ASO-PCR pre IM treatment and post nilotinib treatment results showed the presence of the T315I mutation (Figure 3, (Figure 4). The final karyotype pre IM treatment and post nilotinib treatment was determined:Figure 1


Hyperdiploidy associated with T315I mutation in BCR-ABL kinase domain in an accelerated phase-chronic myeloid leukemia case.

Al-Achkar W, Moassass F, Ikhtiar A, Liehr T, Othman MA, Wafa A - Mol Cytogenet (2014)

ASO-PCR monitoring and corresponding sensitivity test for detected T315I mutation Post-nilotinib treatment. Line M, 1 kb DNA ladder; lines 1–8 patients ASO-PCR T315I wild-type primers; P, our patient; lines 9–16 ASO-PCR T315I mutated primers; and P*, our patient with T315I mutation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4305221&req=5

Fig4: ASO-PCR monitoring and corresponding sensitivity test for detected T315I mutation Post-nilotinib treatment. Line M, 1 kb DNA ladder; lines 1–8 patients ASO-PCR T315I wild-type primers; P, our patient; lines 9–16 ASO-PCR T315I mutated primers; and P*, our patient with T315I mutation.
Mentions: Pre IM treatment banding cytogenetics revealed a karyotype of 46,XY,t(9;22)[7]/56,XY,+3,+6,+7,+8,+8,+9,t(9;22),+10,+12,+19,+der(22)t(9;22)[5]/57,XY,+3,+6,+7,+8,+8,+9,t(9;22),+10,+12,+15,-18,+19,+der(22)t(9;22)x2[8]. Post nilotinib treatment banding cytogenetics revealed a karyotype of 46,XY,t(9;22)[1]/46,XY[39] (Figure 1). Further studies were done based on molecular cytogenetics (Figure 2) and molecular genetics (Figure 3). Dual-color-FISH pre IM treatment; using a specific probe for BCR and ABL1 revealed onefusion signal on the derivative chromosomes 9 [der(9)] and another three fusion signals on the up to three Ph chromosomes (Figure 2); and chromosomes 3, 6, 7, 8, 9, 10, 12, 15, 19 and 22, were studied with WCP and/or CEP probes and did not provide any hint on cryptic translocations (data not shown). RT-PCR pre IM treatment and post nilotinib treatment confirmed the presence of the BCR-ABL1 fusion (b3a2 transcript) revealing a major M-BCR transcript (data not shown). RQ-PCR post nilotinib treatment demonstrated a ratio of BCR-ABL/ABL1 expression of 0.07% on IS (data not shown). ASO-PCR pre IM treatment and post nilotinib treatment results showed the presence of the T315I mutation (Figure 3, (Figure 4). The final karyotype pre IM treatment and post nilotinib treatment was determined:Figure 1

Bottom Line: A complete cytogenetic and molecular cytogenetic analysis; molecular biology methods such as quantitative reverse transcription polymerase chain reaction (RQ-PCR) and allele-specific oligonucleotide (ASO)-PCR; and immunophenotypically confirmed CML in acceleration phase (AP).The patient demonstrated a good response to nilotinib after imatinib failure; while the hyperdiploid clone disappeared the T315I mutation remained during follow-up.The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.

View Article: PubMed Central - PubMed

Affiliation: Human Genetics Division, Department of Molecular Biology and Biotechnology, Atomic Energy Commission, P.O. Box 6091 Damascus, Syria.

ABSTRACT

Background: Chronic myeloid leukemia (CML) is genetically characterized by the occurrence of a reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL gene fusion on the derivative chromosome 22, i.e. the Philadelphia (Ph) chromosome. During CML progression 60-80% of the cases acquire additional genetic changes. Even though hyperdiploidy is not a rare finding in advanced phase-CML, hyperdiploidy together with a T315I kinase domain (KD) mutation in the BCR-ABL gene has not yet been reported.

Results: A complete cytogenetic and molecular cytogenetic analysis; molecular biology methods such as quantitative reverse transcription polymerase chain reaction (RQ-PCR) and allele-specific oligonucleotide (ASO)-PCR; and immunophenotypically confirmed CML in acceleration phase (AP). Our case revealed the presence of hyperdiploidy including multiple copies of the Ph chromosome, presence of b3a2 fusion transcript,T315I mutation in BCR-ABL KD in pre imatinib mesylate (IM) treatment. The ratio of BCR-ABL/ABL expression in post nilotinib treatment was 0.07% on international scale.

Conclusions: The patient demonstrated a good response to nilotinib after imatinib failure; while the hyperdiploid clone disappeared the T315I mutation remained during follow-up. The underlying mechanisms and prognostic implications of these cytogenetic abnormalities are discussed.

No MeSH data available.


Related in: MedlinePlus