Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm accounting for ∼15% of all leukemia. Progress of the disease from an indolent chronic phase to the more aggressive accelerated phase or blast phase (BP) occurs in a minority of cases and is associated with an accumulation of somatic mutations. We performed genetic profiling of 85 samples and transcriptome profiling of 12 samples from 59 CML patients. We identified recurrent somatic mutations in ABL1 (37%), ASXL1 (26%), RUNX1 (16%), and BCOR (16%) in the BP and observed that mutation signatures in the BP resembled those of acute myeloid leukemia (AML). We found that mutation load differed between the indolent and aggressive phases and that nonoptimal responders had more nonsilent mutations than did optimal responders at the time of diagnosis, as well as in follow-up. Using RNA sequencing, we identified other than BCR-ABL1 cancer-associated hybrid genes in 6 of the 7 BP samples. Uncovered expression alterations were in turn associated with mechanisms and pathways that could be targeted in CML management and by which somatic alterations may emerge in CML. Last, we showed the value of genetic data in CML management in a personalized medicine setting.

Definition, Epidemiology, Pathophysiology, and Essential Criteria for Diagnosis of Pediatric Chronic Myeloid Leukemia

“…Assessment of the following criteria is desirable when CML BCR-ABL1 is diagnosed: (a) for optimal monitoring of treatment response in individual patients: gender, age, height, bodyweight in correlation to the TKI dose administered [ 108 ], identification of mutations in the BCR-ABL1 kinase domain in patients with CML-AP and CML-BP, identification of the BCR-ABL1 breakpoint on a genomic (DNA) level [ 63 , 66 , 109 , 110 , 111 , 112 ], (b) to compare data on pediatric CML BCR-ABL1 internationally: a threphine biopsy (degree of fibrosis, nests of blasts), due to the rarity of pediatric CML all patients should be enrolled in trials and enrolled into the international pediatric CML registry [ 4 ], for comparison of BCR-ABL1 mRNA levels when assessing the treatment response, data derived from individual laboratories must be aligned to a reference method (International Standard, IS) applying laboratory-specific conversion factors [ 113 , 114 ], (c) to improve the scientific understanding of the disease: identification of genes and their products influencing TKI blood serum concentration and metabolism [ 108 , 115 ], assessment of acquired von Willebrand disease in cases with elevated platelets [ 73 , 81 ], vaccination status at diagnosis and maintenance of immunity under TKI treatment [ 116 , 117 , 118 ], identification of somatic or germline mutations and epigenetic modification in addition to BCR-ABL1 [ 55 , 57 , 66 , 112 , 119 , 120 , 121 , 122 ]. …”

“…(c) to improve the scientific understanding of the disease: identification of genes and their products influencing TKI blood serum concentration and metabolism [ 108 , 115 ], assessment of acquired von Willebrand disease in cases with elevated platelets [ 73 , 81 ], vaccination status at diagnosis and maintenance of immunity under TKI treatment [ 116 , 117 , 118 ], identification of somatic or germline mutations and epigenetic modification in addition to BCR-ABL1 [ 55 , 57 , 66 , 112 , 119 , 120 , 121 , 122 ]. …”

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

“…The most common alterations in MBP are those of epigenetic regulator ASXL1 and tumor suppressor genes, such as tumor protein 53 (TP53; up to 20% of cases) and runt-related transcription factor 1 (RUNX1; ≈ 40% of cases). In LBP, the most frequent mutations occur in cyclin dependent kinase inhibitor 2A/B gene (CDKN2A/B; 50% of cases) and IKAROS family zinc finger 1 (IKZF1; 55% of cases) genes [32][33][34]. CDKN2A/B gene encodes proteins involved in p53 and cyclin dependent kinases (CDKs) regulation, indicating its role as tumor suppressor [35].…”

Análise de mutações do domínio BCR-ABL quinase em pacientes com leucemia mielóide crônica refratários ao tratamento com mesilato de imatinibe

“…A Leucemia Mielóide Crônica (LMC) é uma doença mieloproliferativa clonal de células progenitoras hematopoiéticas, com incidência de 0,9 a 1,1 casos por 100 mil habitantes/ano, sendo predominante em adultos do sexo masculino 1,2 . A LMC é caracterizada por uma translocação recíproca entre os cromossomos 9 e 22, que resulta no oncogene BCR-ABL1, responsável por codificar uma proteína tirosina quinase hiperativa, que estimula a proliferação e a resistência à morte celular 3 .…”

“…As primeiras terapias desenvolvidas para a LMC estavam limitadas a agentes inespecíficos como hidroxiuréia, bussulfan ou interferon-alfa (IFNα). No entanto, com o entendimento da patogênese dessa doença, o tratamento de primeira linha para passou a ser realizado com o mesilato de imatinibe (IM), um inibidor de tirosina quinase (ITK), que tem como alvo terapêutico o gene BCR-ABL1, permitindo uma maior sobrevida global para esses pacientes 2,4 . Todavia, mesmo com o surgimento de novas alternativas terapêuticas, com uma resposta mais rápida e profunda, aproximadamente 40% dos pacientes são refratários a medicação e avançam para a fase acelerada (FA) e/ou fase blástica (FB), estando associado a um acúmulo de mutações 5 .…”