Letters to the Editor15/17 TRANSLOCATION, A CONSISTENT CHROMOSOMAL CHANGE IN ACUTE PROMYELOCYTIC LEUKAEMIA
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Acute promyelocytic leukemia: A paradigm of cure by targeted therapies
2023, Bulletin de l'Academie Nationale de MedecineLa leucémie aiguë promyélocytaire (LAP) était l’une des formes les plus rapidement létales de leucémies. Grâce à une succession de révolutions cliniques et biologiques, la très grande majorité des patients est désormais guérie via une combinaison de thérapies ciblées. La découverte de PML/RARA résultant de la translocation t(15,17), initiatrice de la LAP, et de l’efficacité de l’acide tout trans rétinoïque (ATRA) ont permis la première avancée majeure vers un traitement curatif. Cependant, c’est la mise en place d’une thérapie combinée d’ATRA et d’arsenic qui a conduit à la guérison de la quasi-totalité des patients. Ce succès clinique s’est accompagné de découvertes biologiques majeures démontrant les rôles clefs de la dégradation de PML/RARA par les médicaments et celui de la sénescence dépendante de PML en aval de celle-ci. La compréhension du mécanisme de la guérison a ouvert des portes pour comprendre les implications de PML et de RARA (et leur ciblage par l’arsenic et l’acide rétinoïque) dans d’autres hémopathies que les LAP.
Acute promyelocytic leukemia (APL) was considered one the most rapidly lethal acute leukemia. Thanks to multiple breakthroughs, the vast majority of patients are now cured via a combination of targeted therapies. The discovery of the t(15,17) translocation yielding PML/RARA and the efficacy of all trans retinoic acid (ATRA) were the first major contributions towards more efficient therapies and their mechanistic understanding. However, it is the addition of another compound, arsenic, that led to the cure of virtually all APL patients. This clinical success has yielded major biological insights into therapy efficacy by demonstrating the key role of PML/RARA degradation by these two drugs as well as downstream PML-driven senescence. Unravelling the molecular basis of APL cure has also paved the way to the recent understanding of PML and RARA roles (and their respective targeting by arsenic and ATRA) in other hematological malignancies.
Molecular testing in acute myeloid leukemia
2023, Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second EditionAcute myeloid leukemia (AML) diagnosis is increasingly based on the underlying genetic characteristics. While conventional cytogenetic analysis still comprises the backbone of AML classification, evaluation of numerous gene mutations is standard of care for diagnosis, prognostic stratification, and differentially tailored treatment strategies. Genomic technologies have rapidly increased our understanding of the molecular pathogenesis of AML, and this new information is being actively evaluated in comprehensive mutation panels with promise to further improve patient outcomes.
Therapeutic developments in hematology in the 21<sup>st</sup> century
2022, Bulletin de l'Academie Nationale de MedecineLes progrès achevés en hématologie à la fin du XXe siècle et au cours des premières années du XXIe siècle ont été considérables. Elles ont été essentiellement dues au fait que les cellules sanguines chez les patients atteints d’hémopathies malignes, peuvent facilement être prélevées et étudiées. Des progrès méthodologiques majeurs ont été réalisés en cytogénétique avec l’utilisation de la fluorescence in situ, en immunophénotypage avec des cytomètres de flux à 8 et 10 couleurs, en biologie moléculaire avec la découverte de nombreux oncogènes et marqueurs moléculaires tumoraux par « Polymerase Chain reaction » (PCR) et plus récemment avec l’utilisation du séquençage (Next Generation Sequencing NGS). Les cellules tumorales sont aujourd’hui étudiées à l’échelle individuelle. Les patients sont surveillés en continu en fonction de la détection ou non de la maladie résiduelle (MRD) et l’objectif qui était hier d’obtenir des remisions complètes (RC) cytologiques est aujourd’hui remplacé par la nécessité d’obtenir des RC moléculaires sans maladie résiduelle détectable dites RC « MRD négatives ». En parallèle et en partie grâce à ces avancées technologiques, des progrès jusque-là inégalés sont survenus dans le domaine thérapeutique avec l’apparition de thérapeutiques ciblées soit agents chimiques tels les inhibiteurs de tyrosine kinase largement utilisés pour le traitement des leucémies chroniques et dans une moindre mesure leucémies aiguës myéloblastiques, soit immunothérapies (anticorps monoclonaux combinés à des toxiques antitumoraux, anticorps monoclonaux bispécifiques, CAR-T cells, etc.) pour les leucémies aiguës lymphoblastiques, lymphomes et myélomes. Les greffes de cellules souches hématopoiétiques ont également évolué dans de larges proportions. Près de 50 000 greffes sont réalisées chaque année dans le monde (60 % autogreffes, 40 % allogreffes). Les cellules souches sont aujourd’hui en majorité (80 %) prélevées par cytaphérèses dans le sang périphérique alors que la moelle osseuse était la source privilégiée au XXe siècle. Les conditionnements prégreffe sont dans la majorité des cas des conditionnements atténués et la mortalité liée à la greffe a chuté considérablement. Surtout il est devenu possible de trouver un donneur pour pratiquement chaque indication grâce au fichier international de donneurs volontaires non apparentés et surtout grâce à la possibilité récente (depuis 2005) de réaliser les greffes à partir de donneurs intrafamiliaux haploidentiques. De ce fait les greffes tendent de plus en plus à être intrafamiliales. L’avenir des greffes est en constante discussion face au développement des thérapeutiques ciblées et nul ne peut prédire avec clarté la place qu’elles auront conservé dans 5 ans.
The progress achieved in hematology at the end of the 20th century and during the first years of the 21st century was considerable. This probably was mainly due to the fact that blood cells from patients with hematological malignancies can easily be collected and studied. Major methodological progress has been made in cytogenetics with the use of in situ fluorescence, in immunophenotyping with 8 and 10 color flow cytometers, in molecular biology with the discovery of numerous oncogenes and tumor molecular markers by Polymerase Chain reaction (PCR) and more recently with the use of Next Generation Sequencing (NGS). Tumor cells are now studied on an individual scale. Patients are continuously monitored according to the detection or not of minimal residual disease (MRD) and the objective which was yesterday to obtain complete cytological remissions (CR) is today replaced by the need to obtain molecular CR without detectable residual disease called “MRD negative” CRs. In parallel and in part thanks to these technological advances, hitherto unequaled progress has occurred in the therapeutic field with the appearance of targeted therapies, either chemical agents such as tyrosine kinase inhibitors, widely used for the treatment of chronic leukemia and, to a lesser extent acute myeloblastic leukemias, or immunotherapies (monoclonal antibodies combined with antitumor toxins, bispecific monoclonal antibodies, CAR-T cells, etc.) for acute lymphoblastic leukemias, lymphomas and myelomas. Hematopoietic stem cell transplants have also evolved in large proportions. Nearly 50,000 transplants are performed each year worldwide (60% autografts, 40% allografts). Stem cells are now mostly (80%) collected by cytapheresis from peripheral blood, whereas bone marrow was the preferred source in the 20th century. Pre-graft conditioning is now in most cases attenuated (Reduced intensity conditioning “RIC”) and graft-related mortality has dropped considerably. Above all, it has become possible to find a donor for practically every indication thanks to the international file of unrelated voluntary donors and above all thanks to the recent possibility (since 2005) of carrying out transplants from haploidentical intra-family donors with the use of high dose cytoxan. As a result, transplants increasingly tend to be intrafamilial. The future of transplants is under constant discussion in the face of the development of targeted therapies and no one can predict with any clarity the place they will have retained in 5 years.
Precision medicine in myeloid malignancies
2022, Seminars in Cancer BiologyMyeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) “Achilles heels” that can further improve myeloid cancer therapy.
Mechanical phenotyping reveals unique biomechanical responses in retinoic acid-resistant acute promyelocytic leukemia
2022, iScienceAll-trans retinoic acid (ATRA) is an essential therapy in the treatment of acute promyelocytic leukemia (APL), but nearly 20% of patients with APL are resistant to ATRA. As there are no biomarkers for ATRA resistance that yet exist, we investigated whether cell mechanics could be associated with this pathological phenotype. Using mechano-node-pore sensing, a single-cell mechanical phenotyping platform, and patient-derived APL cell lines, we discovered that ATRA-resistant APL cells are less mechanically pliable. By investigating how different subcellular components of APL cells contribute to whole-cell mechanical phenotype, we determined that nuclear mechanics strongly influence an APL cell’s mechanical response. Moreover, decondensing chromatin with trichostatin A is especially effective in softening ATRA-resistant APL cells. RNA-seq allowed us to compare the transcriptomic differences between ATRA-resistant and ATRA-responsive APL cells and highlighted gene expression changes that could be associated with mechanical changes. Overall, we have demonstrated the potential of “physical” biomarkers in identifying APL resistance.
Identification of variant APL translocations PRKAR1A-RARα and ZBTB16-RARα (PLZF-RARα) through the MI-ONCOSEQ platform
2021, Cancer GeneticsThe cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1–2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.