PRE-EXISTING SOMATIC MUTATIONS IN GENES COMMONLY MUTATED IN MYELOID MALIGNANCIES (RUNX1, DNMT3A, ASXL1) MAY CONFER BAD PROGNOSIS IN CHRONIC MYELOID LEUKEMIA.
(Abstract release date: 05/19/16)
EHA Library. Machnicki M. 06/09/16; 132635; E1086
Mr. Marcin Machnicki
Contributions
Contributions
Abstract
Abstract: E1086
Type: Eposter Presentation
Background
Chronic Myeloid Leukemia is readily manageable disease for majority of patients. However, a subset of patients either never achieve or lose response to tyrosine kinase inhibitors (TKIs) and progress from chronic (CML-CP) to blastic phase (CML-BP). The genetic basis of this transition remains only partially understood, particularly when loss of TKI sensitivity cannot be attributed solely to BCR-ABL1 mutations.
Aims
We sought to determine the genetic background of CML progression in patients who experienced TKI treatment failure not associated with BCR-ABL1 mutations using targeted enrichment and next-generation sequencing strategy.
Methods
Sequential DNA samples were collected from 9 patients who were diagnosed in CML-CP and progressed to CML-BP (8 myeloid, 1 lymphoid). SeqCapEZ Choice (NimbleGen) enrichment was used to capture coding sequences of 952 genes (7Mb) implicated in human cancer (with focus on hematological malignancies), followed by high-throughput sequencing on Illumina HiSeq 1500 (>90% ge20, >100x mean coverage).
Results
In 7 patients we observed variants in RUNX1, DNMT3A, ASLX1, PTPN11 and IDH1 genes (table), all of which were considered as damaging and located in previously known hotspots (except for novel DNMT3A mutations). Almost all variants could be detected at CML-CP at varying allele frequency, thus preceding diagnosis of CML progression.
Conclusion
Our results suggest that in rare, refractory CML cases mutations in genes frequently mutated in myeloid neoplasms might cause or contribute to an aggressive CML phenotype. Early detection of such genetic lesions might be important for patients who will not achieve remission with currently available standard treatment regimens and who should be considered as high-risk patients.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, CML blast crisis, Mutation analysis, Progression
Type: Eposter Presentation
Background
Chronic Myeloid Leukemia is readily manageable disease for majority of patients. However, a subset of patients either never achieve or lose response to tyrosine kinase inhibitors (TKIs) and progress from chronic (CML-CP) to blastic phase (CML-BP). The genetic basis of this transition remains only partially understood, particularly when loss of TKI sensitivity cannot be attributed solely to BCR-ABL1 mutations.
Aims
We sought to determine the genetic background of CML progression in patients who experienced TKI treatment failure not associated with BCR-ABL1 mutations using targeted enrichment and next-generation sequencing strategy.
Methods
Sequential DNA samples were collected from 9 patients who were diagnosed in CML-CP and progressed to CML-BP (8 myeloid, 1 lymphoid). SeqCapEZ Choice (NimbleGen) enrichment was used to capture coding sequences of 952 genes (7Mb) implicated in human cancer (with focus on hematological malignancies), followed by high-throughput sequencing on Illumina HiSeq 1500 (>90% ge20, >100x mean coverage).
Results
In 7 patients we observed variants in RUNX1, DNMT3A, ASLX1, PTPN11 and IDH1 genes (table), all of which were considered as damaging and located in previously known hotspots (except for novel DNMT3A mutations). Almost all variants could be detected at CML-CP at varying allele frequency, thus preceding diagnosis of CML progression.
| Patient | Mutation(s) | NCBI Reference | Pre-existing in CML-CP? | Allele frequency | Allele frequency | CML-BP type | ||
| CML-CP | CML-BP(s) | |||||||
| 1 | RUNX1 R230* | NM_001754.4 | Yes | 1% | 39% | 46% | 18% | lymphoid |
| 2 | IDH1 R132S | NM_005896.3 | Yes | 8% | 52% | myeloid | ||
| 3 | RUNX1 R166L E202_P203ins | NM_001754.4 NM_001754.4 | No No | 0% 0% | 34% 18% | myeloid | ||
| 4 | DNMT3A Y481* PTPN11 A72V | NM_175629.2 NM_002834.3 | Yes No | 52% 0% | 54% 45% | myeloid | ||
| 5 | RUNX1 E316_L317fs | NM_001754.4 | Yes | 17% | 18% | myeloid | ||
| 6 | DNMT3A L798F ASXL1 G643_G644fs | NM_175629.2 NM_015338.5 | Yes Yes | 50% 21% | 57% 40% | myeloid | ||
| 7 | ASXL1 G626_A627fs | NM_015338.5 | Yes | 39% | 22% | myeloid | ||
Conclusion
Our results suggest that in rare, refractory CML cases mutations in genes frequently mutated in myeloid neoplasms might cause or contribute to an aggressive CML phenotype. Early detection of such genetic lesions might be important for patients who will not achieve remission with currently available standard treatment regimens and who should be considered as high-risk patients.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, CML blast crisis, Mutation analysis, Progression
Abstract: E1086
Type: Eposter Presentation
Background
Chronic Myeloid Leukemia is readily manageable disease for majority of patients. However, a subset of patients either never achieve or lose response to tyrosine kinase inhibitors (TKIs) and progress from chronic (CML-CP) to blastic phase (CML-BP). The genetic basis of this transition remains only partially understood, particularly when loss of TKI sensitivity cannot be attributed solely to BCR-ABL1 mutations.
Aims
We sought to determine the genetic background of CML progression in patients who experienced TKI treatment failure not associated with BCR-ABL1 mutations using targeted enrichment and next-generation sequencing strategy.
Methods
Sequential DNA samples were collected from 9 patients who were diagnosed in CML-CP and progressed to CML-BP (8 myeloid, 1 lymphoid). SeqCapEZ Choice (NimbleGen) enrichment was used to capture coding sequences of 952 genes (7Mb) implicated in human cancer (with focus on hematological malignancies), followed by high-throughput sequencing on Illumina HiSeq 1500 (>90% ge20, >100x mean coverage).
Results
In 7 patients we observed variants in RUNX1, DNMT3A, ASLX1, PTPN11 and IDH1 genes (table), all of which were considered as damaging and located in previously known hotspots (except for novel DNMT3A mutations). Almost all variants could be detected at CML-CP at varying allele frequency, thus preceding diagnosis of CML progression.
Conclusion
Our results suggest that in rare, refractory CML cases mutations in genes frequently mutated in myeloid neoplasms might cause or contribute to an aggressive CML phenotype. Early detection of such genetic lesions might be important for patients who will not achieve remission with currently available standard treatment regimens and who should be considered as high-risk patients.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, CML blast crisis, Mutation analysis, Progression
Type: Eposter Presentation
Background
Chronic Myeloid Leukemia is readily manageable disease for majority of patients. However, a subset of patients either never achieve or lose response to tyrosine kinase inhibitors (TKIs) and progress from chronic (CML-CP) to blastic phase (CML-BP). The genetic basis of this transition remains only partially understood, particularly when loss of TKI sensitivity cannot be attributed solely to BCR-ABL1 mutations.
Aims
We sought to determine the genetic background of CML progression in patients who experienced TKI treatment failure not associated with BCR-ABL1 mutations using targeted enrichment and next-generation sequencing strategy.
Methods
Sequential DNA samples were collected from 9 patients who were diagnosed in CML-CP and progressed to CML-BP (8 myeloid, 1 lymphoid). SeqCapEZ Choice (NimbleGen) enrichment was used to capture coding sequences of 952 genes (7Mb) implicated in human cancer (with focus on hematological malignancies), followed by high-throughput sequencing on Illumina HiSeq 1500 (>90% ge20, >100x mean coverage).
Results
In 7 patients we observed variants in RUNX1, DNMT3A, ASLX1, PTPN11 and IDH1 genes (table), all of which were considered as damaging and located in previously known hotspots (except for novel DNMT3A mutations). Almost all variants could be detected at CML-CP at varying allele frequency, thus preceding diagnosis of CML progression.
| Patient | Mutation(s) | NCBI Reference | Pre-existing in CML-CP? | Allele frequency | Allele frequency | CML-BP type | ||
| CML-CP | CML-BP(s) | |||||||
| 1 | RUNX1 R230* | NM_001754.4 | Yes | 1% | 39% | 46% | 18% | lymphoid |
| 2 | IDH1 R132S | NM_005896.3 | Yes | 8% | 52% | myeloid | ||
| 3 | RUNX1 R166L E202_P203ins | NM_001754.4 NM_001754.4 | No No | 0% 0% | 34% 18% | myeloid | ||
| 4 | DNMT3A Y481* PTPN11 A72V | NM_175629.2 NM_002834.3 | Yes No | 52% 0% | 54% 45% | myeloid | ||
| 5 | RUNX1 E316_L317fs | NM_001754.4 | Yes | 17% | 18% | myeloid | ||
| 6 | DNMT3A L798F ASXL1 G643_G644fs | NM_175629.2 NM_015338.5 | Yes Yes | 50% 21% | 57% 40% | myeloid | ||
| 7 | ASXL1 G626_A627fs | NM_015338.5 | Yes | 39% | 22% | myeloid | ||
Conclusion
Our results suggest that in rare, refractory CML cases mutations in genes frequently mutated in myeloid neoplasms might cause or contribute to an aggressive CML phenotype. Early detection of such genetic lesions might be important for patients who will not achieve remission with currently available standard treatment regimens and who should be considered as high-risk patients.
Session topic: E-poster
Keyword(s): Chronic myeloid leukemia, CML blast crisis, Mutation analysis, Progression
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