Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Abstract

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis. (Blood. 2007;110: [1648][1649][1650][1651][1652][1653][1654][1655]

Acquired copy number alterations in adult acute myeloid leukemia genomes

“…Normal skin DNA was available from 1 of 3 patients (2 CALGB samples had no normal DNA available) and confirmed that R105Q was an acquired (somatic) mutation not previously described. We also identified mutations in WT1, and sequencing results from 37 additional genes have previously been reported (Table S1 and SI Methods) (21,22).…”

“…Standard reverse transcription was performed using 1 g of total RNA. Exonic gene resequencing was performed as previously described (primer sequences available upon request) (21,22).…”

Prevalence of a new auto-activating colony stimulating factor 3 receptor mutation (CSF3R-T595I) in acute myeloid leukemia and severe congenital neutropenia

“…[6][7][8] In contrast, such CSF3R nonsense mutations have not been reported in de novo AML. [9][10][11] We recently identified a new extracellular CSF3R mutation (T595I) in the leukemic blasts of a SCN patient after progression to AML. 12 This mutation, located on the CSF3R allele that already carried the nonsense mutation, causes fully autonomous, i.e.…”

Germline Genetic Predisposition to Hematologic Malignancy

“…The clinical implications of clonal cytogenetic abnormalities or somatic mutations with clonal hematopoiesis may differ in the context of these syndromes, and additional studies are needed. 3,4 In addition, many syndromes are associated with bone marrow failure (BMF), which responds poorly to standard treatment with antithymocyte globulin and cyclosporine and, thus, would require a different treatment approach compared with the patient with acquired aplastic anemia. Similarly, some germline disorders conditioning regimens may require reduced-intensity conditioning approaches for hematopoietic stem cell transplant.…”