Subject(s)
Clonal Evolution/genetics , Gene Rearrangement , Immunoglobulin Heavy Chains/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Biomarkers, Tumor , Biopsy , Bone Marrow/metabolism , Chromosome Aberrations , Disease Progression , Female , High-Throughput Nucleotide Sequencing , Humans , Immunophenotyping/methods , Middle Aged , Neoplasm, Residual/diagnosisSubject(s)
Antibodies, Monoclonal/adverse effects , Antigens, CD19/immunology , Gene Rearrangement , Histone-Lysine N-Methyltransferase/genetics , Immunotherapy/adverse effects , Leukemia, Myeloid, Acute/pathology , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Female , Humans , Leukemia, Myeloid, Acute/chemically induced , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , PrognosisABSTRACT
Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (KIT, NRAS, KRAS, FLT3, JAK2, CBL). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age (P = .004) and inv(16) subtype (P = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference (P = .14). The repertoire of KIT, FLT3, and NRAS/KRAS variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival (P < 10-4), whereas the presence of a single signaling clone did not (P = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.
Subject(s)
Clonal Evolution/genetics , Core Binding Factors/metabolism , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/metabolism , Mutation , Signal Transduction , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Child , Child, Preschool , Chromosome Aberrations , Female , Gene Expression Regulation, Leukemic , High-Throughput Nucleotide Sequencing , Humans , Infant , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Analysis , Young AdultABSTRACT
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis that should be investigated in routine practice. Single-nucleotide polymorphism (SNP)-array provides a useful method to detect such cases showing a highly characteristic profile.