Abstract
After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.
Highlights
After decades during which the treatment of acute myeloblastic leukemia (AML) was based on variants of the classic “7 + 3” cytarabine/daunorubicin association, progresses in molecular biology by generation sequencing (NGS) have made possible to discover numerous drugable mutations leading to the notion of targeted therapies.The next generation sequencing (NGS) techniques, called “massively parallel sequencing” or “deep sequencing”, can analyze millions of Desoxyribonucleic acid (DNA) or Ribonucleic acid (RNA) fragments in parallel
There are many objections to this concept, notably the observations resulting from the various single cell experiments that allow the study of transcribed RNA and of the DNA sequences themselves on a cell-by-cell basis
In the sense of t-distributed stochastic neighbor embedding (t-SNE) analysis, is an approach that reduces the dimensionality of blast cells high-dimensional data and enables the data to be visualized in two-dimensional space
Summary
After decades during which the treatment of acute myeloblastic leukemia (AML) was based on variants of the classic “7 + 3” cytarabine/daunorubicin association (apart from the specific treatment of promyelocytic AML), progresses in molecular biology by generation sequencing (NGS) have made possible to discover numerous drugable mutations leading to the notion of targeted therapies.The NGS techniques, called “massively parallel sequencing” or “deep sequencing”, can analyze millions of DNA or RNA fragments in parallel. The first step of NGS is the random DNA fragmentation followed by binding to specific small sequences, followed by amplification of this bank using clonal amplification and PCR methods, the sequencing is performed, usually by the sequencing synthesis (SBS) technique (for a review, [1]) This technology allows sequencing a whole exome (22,000 coding genes) within a single day, while the classical Sanger technique would require months or years. The NGS has many advantages over conventional techniques It allows the detection of all mutations and single nucleotide polymorphisms (SNIPs) in a given cell population without the need to define a priori the target genes. This technique has a high sensibility allowing sequencing even very small cellular subpopulations. The ultimate goals of this project is to identify predictive markers, to understand the key features of previously described transition states, and the to identify relevant therapeutic targets in order to elaborate specific treatment strategy at the individual level, i.e precision-medicine treatment designed to fit with both the tumor and the patient [2]
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