Classical cytogenetics (CC) encompassing fluorescence in situ hybridisation (FISH) and karyotype remains central to the diagnostic work-up of non-Hodgkin lymphoma (NHL). However, karyotype is limited by restricted access to fresh tumour tissue and low resolution, while FISH provides targeted information. Optical genome mapping (OGM) has emerged as a genome-wide, high-resolution approach capable of detecting both translocations and copy number variations in a single assay. To assess its feasibility and diagnostic performance in routine practice, we prospectively compared OGM to CC in 105 patients with NHL. OGM was technically feasible in both fresh and frozen tissue specimens. Among 511 cytogenetic abnormalities (CAs) directly compared, 91.1% were concordant between the two methods. Using the low allele fraction guided assembly pipeline, OGM identified all 77 immunoglobulin loci rearrangements, with a sensitivity threshold of 5%. Overall, OGM detected diagnostically relevant CAs in 99/105 patients (94.2%). OGM outperformed CC in 10/105 patients (9.5%), revealing cryptic rearrangements involving major target genes (MYC, BCL2 and BCL6) as well as diagnostically relevant CAs in cases with uncertain diagnoses or non-informative karyotypes. In conclusion, OGM demonstrated feasibility in routine practice and superior diagnostic performance compared with CC, supporting its integration into the standard genetic work-up of NHL.

Objectives Although flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression can accurately rule out myelodysplastic neoplasms (MDS), it lacks reliability and efficiency due to the practical limitations of laboratory-developed liquid reagent-based assays. This study aimed to quantify the agreement and comparative discriminatory accuracy between a single-use flow cytometric lyophilised reagent tube (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart.Design Cross-sectional diagnostic accuracy study of two index tests against a reference diagnosis.Setting A university hospital in France.Participants Consecutive adult patients with an indication for bone marrow aspiration due to suspected MDS and unexplained peripheral blood cytopenia.Primary outcome MDS confirmed by cytomorphological evaluation of the bone marrow aspirate performed in duplicate by experienced haematopathologists blinded to the index test.Results Of 103 participants enrolled between July 2020 and August 2021, 37 had MDS (prevalence, 36%). The median intra-individual robust coefficient of variation (RCV) for myeloperoxidase expression was 30.9% using the BD Lyotube Stain 468 and 31.2% using the laboratory-developed liquid reagent assay, with an intraclass correlation coefficient of 0.94 (95% CI 0.91 to 0.96). The areas under the receiver operating characteristic curves were 0.83 (95% CI 0.74 to 0.90) and 0.82 (95% CI 0.73 to 0.89), respectively. Using a prespecified threshold of 30.0%, the corresponding sensitivity estimates were 89% (95% CI 75% to 97%) and 95% (95% CI 82% to 99%).Conclusion BD Lyotube Stain 468 performs as well as its laboratory-developed liquid reagent counterpart for the quantification of myeloperoxidase expression by peripheral blood neutrophils. It may obviate the need for invasive bone marrow aspiration in up to 40% of patients with suspected MDS.Trials registration number NCT04399018.

t(X;20)(q13;q13) is a very rare but recurrent translocation observed in myeloid neoplasms such as myelodysplastic neoplasm (MDS), myeloproliferative neoplasm (MPN), and acute myeloid leukemia (AML). While only nine cases have been reported previously,1-5 we have collected data (including gene sequencing data) on a large series of 25 cases of myeloid neoplasms with t(X;20). By retrospectively screening databases at 13 French cytogenetic laboratories, we identified 25 cases of t(X;20)(q13;q13) (Figure 1A,B; Table S1). The study was approved by the local institutional review board (AP-HP (Paris, France); reference: BPD2018DIA008) and complied with the tenets of the Declaration of Helsinki. All the patients provided their written, informed consent to participation. Bone marrow smears (available for 16 of the 25 patients) were blind-reviewed by two independent expert cytologists (J-FL and CS). To obtain R- or G-banded chromosomes, cells were prepared from bone marrow using standard techniques. All the karyotypes were reviewed by the members of the Groupe Francophone de Cytogénétique Hématologique and classified according to the International System for Human Cytogenetic Nomenclature (ISCN 2020). A complex karyotype was defined as the presence of three or more clonal chromosomal abnormalities (CAs). Standard fluorescence in situ hybridization was performed on metaphase and interphase nuclei, using the commercial probes XIST (Xq13.2)/CCPX (CytoTest, Rockville, MD, USA), 20q12 (PTPRT)/20q13 (MYBL2) (Cytocell, Cambridge, UK), WCP20 and WCPX (Metasystems, Altlußheim, Germany). Fourteen patient samples were sequenced with a next-generation sequencing myeloid panel (Supplemental Information). For one center (Pitié-Salpêtrière, between 2015 and 2022), we were able to calculate the exact prevalence of t(X;20) in MDS (0.4%; 2 out of 421) and in MDS or unexplained cytopenia (0.1%; 2 out of 1283). All 25 patients were female. The median age was 78 (range: 60–91). Five of the 23 patients with available clinical data had received chemotherapy for follicular lymphoma (case #1), multiple myeloma (case #16), breast cancer (case #19), ovarian cancer (case #14) or AML (case #24) before the t(X;20) was detected. The initial diagnoses were MDS (n = 12, including ring sideroblasts in cases #2, #8, and #18), cytopenia (n = 6), AML (n = 3), and MPN with eosinophilia (n = 1). Three myelograms were hemodiluted so a morphologic diagnosis could not be made. The morphologic review of 16 samples confirmed the diagnoses for 11 cases of MDS and one case of AML and led to the reclassification of two out of four cases of cytopenia as unclassifiable MDS (MDS-U, cases #6 and #21) (Figure S1). The two reviewers observed an abnormal chromatin clumping in 6/16 (37%) cases, but no specific feature of the t(X;20). Finally, the four remaining cases of cytopenia were considered to be clonal cytopenia of undetermined significance (CCUS). In the 14 cases of MDS and 4 cases of CCUS, the karyotype was never complex; the t(X;20) was the only CA in 12 of the 18 cases (67%). In the other 6 cases, the additional CAs were del(5q) (3 out of 18, 17%; none in CCUS), del(20q) (2 out of 18, 11%; none in CCUS), and trisomy (tri) 8 (1 out of 18, 5%). The t(X;20) was subclonal in only one of the 18 cases (5%). In cases presenting with both t(X;20) and del(20q), the two CAs were always in independent clones. All the cases of AML had complex karyotypes with 3 to 7 CAs. The t(X;20) was present in the major clone in all three patients (Tables S1 and S2). In the cohort as a whole, the most common associated CA was del(5q) (6 out of 25, 24%)—which was variously clonal, subclonal, or present in independent clones—and followed by del(20q) (3 out of 25, 12%) or tri8 (2/25, 8%). It is noteworthy that in one patient (case #24), tri8 was present in 24 of the 25 (96%) mitoses observed at the time of AML diagnosis. Four months later (during the first-line treatment), tri8 was still observed in three mitoses independently of t(X;20); this might correspond to residual AML blasts. At relapse 2 years later, tri8 reappeared (additionally with tetrasomy 8), whereas t(X;20) was no longer observed (Figure S2). In all 14 tested cases, the breakpoint on the X chromosome was proximal to XIST (Xq13.2), and the breakpoint on chromosome 20 was distal to MYBL2 on 20q13 (Figure 1C,D). Molecular data revealed mutations in TET2 (n = 7 out of 14, 50%), SF3B1 (n = 3, 21%), DNMT3A (n = 3, 21%), RUNX1 (n = 2, 14%), and U2AF1 (n = 2, 14%) (Table S1). Of note, the 3 patients with SF3B1mut also had a del(5q); and the only CCUS case tested by NGS had mutations in TET2 and DNMT3A. No TP53 mutations were observed. We also detected mutations in SRSF2, BCOR, BCORL1, IDH1, EP300, NRAS, and ETV6 (n = 1 each). Regarding MDS and CCUS, the cytogenetic category for the Revised International Prognostic Scoring System (IPSS-R) score was intermediate in all but the three cases of MDS with t(X;20) and del(5q) (with a favorable score).6 The median MDS IPSS-R score was 2.25 (range, 1–4). Of the 18 scores, 15 (83%) were classified as low risk, one was classified as very low risk, and two were classified as intermediate risk (Table S1 and Figure 1E). With a median follow-up time of 17 months (95% CI: 10–37), the median overall survival was not reached, and 69% of the patients were alive at 5 years. To the best of our knowledge, the present series of t(X;20) cases is the largest yet. As previously described, all patients were female, and the median age was 78. The majority (64%) of t(X;20) cases corresponded to MDS. The morphological evidence for MDS was not always easy to interpret: two of the four morphologically reviewed cases of cytopenia were reclassified as MDS. However, four cases of cytopenia had no morphological evidence of MDS. According to the fourth edition of the World Health Organization's classification of hematolymphoid tumors, t(X;20)(q13;q13) is not one of the CAs that defines MDS-U. In the fifth edition, patients with isolated t(X;20)(q13;q13) are classified as having CCUS. In our series of MDS/CCUS cases, t(X;20) was frequently isolated (in 67% of cases) and was associated with a low-risk MDS IPSS-R in 83% of cases. Overall, t(X;20) was associated with cases of MDS/CCUS (82%) with a favorable prognosis. In a few cases, t(X;20) was observed in AML but only included in a complex karyotype. Our series included a case of MPN with hypereosinophilia. t(X;20) was frequently isolated or present in the major clone, and may be an early event. The most frequent associated CA was del(5q) (24%). Interestingly, when associated with del(20q) (12%), t(X;20) was always present in an independent clone. This is in line with the possible silencing of 20q genes by a position effect of the XIST gene on der(20).2 The spreading of X inactivation to the 20q region provides an alternate mechanism for del(20q).4 Indeed, in all the tested cases, XIST gene was translocated on the der(20), and all 20q genes stayed on the long arm of der(20). In conclusion, t(X;20)(q13;q13) is a rare translocation observed in older women. It may be an early event. t(X;20)(q13;q13) is often isolated and is mostly associated with MDS/CCUS with a favorable prognosis. It is found less frequently in cases of AML and MPN. The most commonly associated CAs are del(5q) and del(20q), and the latter is always in an independent clone. We therefore suggest that isolated t(X;20) should be classified in a good cytogenetic IPSS-R category (score = 1), rather than in an intermediate cytogenetic category (score = 2). F.N-K. and M.M. designed the study. N.A., E.C., M-A.C-R., A.D., V.E., B.G., A.I., C.L., M-J.M., D.P., J.Q., C.T., and L.V. provided samples and clinical data. J-F.L and C.S performed the morphological review. L.S. performed additional FISH analysis. P.H. performed NGS sequencing. E.C. performed statistical analysis. F.N-K., M.M., D.G., and M-B.T. analyzed data. F.N-K. wrote the manuscript. M.M. and M-B.T. reviewed the manuscript. All co-authors approved the manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND:MYC-driven lymphomas are a subset of B-cell lymphomas characterized by genetic alterations that dysregulate the expression of the MYC oncogene. When overexpressed, typically through chromosomal translocations, amplifications, or other mechanisms, MYC can drive uncontrolled cell growth and contribute to cancer development. MYC-driven lymphomas are described as aggressive entities which require intensive treatment approaches and can be associated with poor prognosis. In the absence of direct MYC-targeting therapy, epigenetic drugs called BET inhibitors (BETi) were shown to reduce MYC levels by disrupting BRD4-dependent transcription associated with the expression of MYC, as well as other oncogenes. Here, we used BETi as molecular tools to better understand oncogenic dependencies in a panel of cell line models of MYC-driven B-cell lymphoma selected to represent their genetic heterogeneity. RESULTS:We first showed that, in these models, MYC expression level does not strictly correlate to the presence of gene alterations. Our data also demonstrated that BETi induces similar growth arrest in all lymphoma cell lines independently of MYC mutational status or expression level. In contrast, BETi-induced cell death was only observed in two cell lines presenting the highest level of MYC protein. This suggests that some MYC-driven lymphoma could present a stronger dependency on MYC for their survival which cannot be predicted on the sole basis on their genetics. This hypothesis was confirmed by gene invalidation experiments, which showed that MYC loss recapitulates the effect of BETi treatment on both cell proliferation and survival, confirming MYC oncogene dependency in models sensitive to BETi cytotoxicity. In contrast, the growth arrest observed in cell lines resistant to BETi-induced apoptosis is not mediated through MYC, but rather through alternative pro-proliferative or oncogenic pathways. Gene expression profiling revealed the basal activation of a specific non-canonical WNT/Hippo pathway in cell death-resistant cell lines that could be targeted in combination therapy to restore BETi cytotoxicity. CONCLUSION:This work brings new insights into the complexity of MYC-dependencies and unravels a novel targetable oncogenic pathway in aggressive B-cell lymphomas.

A newborn girl had typical "blueberry muffin" skin lesions, which shows histopathologic features of monocytic leukemia cutis. The systemic leukemia was demonstrated after one month of life. She was treated by chemotherapy, including induction and three consolidation cures, according to the ELAM02 protocol, which led to complete remission. This case report with congenital form of AML5 cutaneous localization, preceding systemic involvement, with a 5-year follow-up and positive outcome is remarkable.

Cytogenetic analysis is mandatory at initial assessment of B-cell acute lymphoblastic leukemia (B-ALL) due to its diagnostic and prognostic value. Results from chromosome banding analysis and complementary FISH are taken into account in therapeutic protocols and further completed by other techniques (RT-PCR, SNP-array, MLPA, NGS, OGM). Indeed, new genomic entities have been identified by NGS, mostly RNA sequencing, such as Ph-like ALL that can benefit from targeted therapy. Here, we have attempted to establish cytogenetic guidelines by reviewing the most recent published data including the novel 5th World Health Organization and International Consensus Classifications. We also focused on newly described cytogenomic entities and indicate alternative diagnostic tools such as NGS technology, as its importance is vastly increasing in the diagnostic setting.

Nada Assaf , Noor Hanania, Christine Lefebvre, Dominique Penther, G eraldine Salmeron, Bruno Petitjean and Christine Terr e Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Lebanon; Laboratoire d’H ematologie Biologique, Centre Hospitalier Universitaire de Grenoble Alpes (CHUGA), France; Laboratoire d’Oncog en etique, Centre Henri Becquerel, Rouen, France; Department of Hematology, Centre Hospitalier de Versailles, Le Chesnay, France; UMR1184, University Paris-Saclay, France; Department of Laboratory Medicine, Hematology, Centre Hospitalier de Versailles, Le Chesnay, France; Anatomie et Cytologie Pathologiques, Centre Hospitalier Intercommunal de Poissy Saint Germain en Laye, France; Department of Laboratory Medicine, Hemato-Oncologic Cytogenetics, Centre Hospitalier de Versailles, Le Chesnay, France

Non-Hodgkin lymphomas (NHL) consist of a wide range of clinically, phenotypically and genetically distinct neoplasms. The accurate diagnosis of mature B-cell non-Hodgkin lymphoma relies on a multidisciplinary approach that integrates morphological, phenotypical and genetic characteristics together with clinical features. Cytogenetic analyses remain an essential part of the diagnostic workup for mature B-cell lymphomas. Karyotyping is particularly useful to identify hallmark translocations, typical cytogenetic signatures as well as complex karyotypes, all bringing valuable diagnostic and/or prognostic information. Besides the well-known recurrent chromosomal abnormalities such as, for example, t(14;18)(q32;q21)/IGH::BCL2 in follicular lymphoma, recent evidences support a prognostic significance of complex karyotype in mantle cell lymphoma and Waldenström macroglobulinemia. Fluorescence In Situ Hybridization is also a key analysis playing a central role in disease identification, especially in genetically-defined entities, but also in predicting transformation risk or prognostication. This can be exemplified by the pivotal role of MYC, BCL2 and/or BCL6 rearrangements in the diagnostic of aggressive or large B-cell lymphomas. This work relies on the World Health Organization and the International Consensus Classification of hematolymphoid tumors together with the recent cytogenetic advances. Here, we review the various chromosomal abnormalities that delineate well-established mature B-cell non-Hodgkin lymphoma entities as well as newly recognized genetic subtypes and provide cytogenetic guidelines for the diagnostic management of mature B-cell lymphomas.

Follicular lymphoid hyperplasia induced by dasatinib is an entity recently described. It is sometimes difficult to rule out the diagnostic of small B-cell lymphoma. Usually, the node is swollen, with follicular architecture conserved, composed by germinal centers with variable size and shape, with a hight number of mitoses and tingible bodies macrophages inside. Follicular lymphoid hyperplasia is isolated or associated with multiple reactive patterns. The immunohistochemical profil of germinal centers is CD20+, CD10+, BCL6+, BCL2-. Swollen node disappears in a short time after dasatinib discontinuation. Clinicians and pathologists need to be aware of this entity, so as not to avoid mistakenly suspect lymphoma when lymphadenopathy occurs in a patient with chronic myeloid leukemia treated with dasatinib. (c) 2022 Elsevier Masson SAS. All rights reserved.

Genetic data are becoming increasingly essential in the management of hematological neoplasms as shown by two classifications published in 2022: the 5th edition of the World Health Organization Classification of Hematolymphoid Tumours and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Genetic data are particularly important for acute myeloid leukemias (AMLs) because their boundaries with myelodysplastic neoplasms seem to be gradually blurring. The first objective of this review is to present the latest updates on the most common cytogenetic abnormalities in AMLs while highlighting the pitfalls and difficulties that can be encountered in the event of cryptic or difficult-to-detect karyotype abnormalities. The second objective is to enhance the role of cytogenetics among all the new technologies available in 2023 for the diagnosis and management of AML.

Objectives Acute myeloid leukemia (AML) with inv(16)/t(16;16) is among the most frequent AML subtypes. It is recognized by the detection of the CBFB-MYH11 fusion which confers a favorable prognosis, irrespective of the presence of secondary cytogenetic abnormalities. However, the effect of additional genetic anomalies on the behavior of inv(16) AML is debatable. Recent case reports describe an unfavorable prognosis for those patients, characterized by early relapse and death. In this study, we present a series of patients with CBFB-MYH11 fusion and high-risk rearrangements to increase knowledge about this potentially distinct subgroup. Methods All cases with inv(16)/ t(16;16) and one or more high risk abnormalities were reviewed at two tertiary healthcare centers between years 2006 and 2020 in terms of demographics, biological and clinical data. Results Among the total 1447 and 1283 AML cases, the frequency was found to be 0,2% and 0.3%. Clinical data could be retrieved for 5 patients. Detected high-risk abnormalities included TP53 and 5q deletion, complex and monosomal karyotype. The median age was 67 years, with a majority of females (M:F = 1:1.5). Two out of 5 patients presented with therapy related AML, with short latency periods. All patients presented with thrombocytopenia and/or leukocytopenia. Bone marrow aspirates revealed atypical morphology and the detection of rare CBFB-MYH11 fusion transcripts. All 5 patients died, with a short mean overall survival of 5.8 months. Discussion and Conclusion Our series suggests that the presence of high risk abnormalities confers distinct biological features and poor prognosis to inv(16) AML.

Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.

INTRODUCTION:Suspicion of myelodysplastic syndromes (MDS) is the most common reason for bone marrow aspirate in elderly patients. Peripheral blood neutrophil myeloperoxidase expression quantified by flow cytometric analysis might rule out MDS for up to 35% of patients referred for suspected disease, without requiring bone marrow aspiration. Yet laboratory-developed liquid antibody cocktails have practical limitations, because of lack of standardisation and poor stability. This research project aims to estimate the level of agreement and comparative accuracy between a single-use flow cytometry tube of lyophilised reagents (BD Lyotube Stain 468) and its laboratory-developed liquid reagent counterpart in quantifying peripheral blood neutrophil myeloperoxidase expression, among adult patients referred for suspected MDS.METHODS AND ANALYSIS:The MPO-MDS-Develop project is a cross-sectional diagnostic accuracy study of two index tests by comparison with a reference standard in consecutive unselected adult patients conducted at a single university hospital. Flow cytometry analysis of peripheral blood samples will be performed by independent operators blinded to the reference diagnosis, using either Lyotube Stain 468 or laboratory-developed liquid reagent cocktail. The reference diagnosis of MDS will be established by cytomorphological evaluation of bone marrow aspirate by two independent haematopathologists blinded to the index test results. Morphologic assessment will be complemented by bone marrow flow cytometric score, karyotype and targeted next-generation sequencing panel of 43 genes, where relevant. The target sample size is 103 patients.ETHICS AND DISSEMINATION:An institutional review board (Comité de Protection des Personnes Sud Est III, Lyon, France) approved the protocol prior to study initiation (reference number: 2020-028-B). Participants will be recruited using an opt-out approach. Efforts will be made to release the primary results within 6 months of study completion.TRIAL REGISTRATION NUMBER:NCT04399018.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.

Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective.

Karyotype complexity has major prognostic value in many malignancies. There is no consensus on the definition of a complex karyotype, and the prognostic impact of karyotype complexity differs from one disease to another. Due to the importance of the complex karyotype in the prognosis and treatment of several hematological diseases, the Francophone Group of Hematological Cytogenetics (Groupe Francophone de Cytogénétique Hématologique, GFCH) has developed an up-to-date, practical document for helping cytogeneticists to assess complex karyotypes in these hematological disorders. The evaluation of karyotype complexity is challenging, and it would be useful to have a consensus method for counting the number of chromosomal abnormalities (CAs). Although it is not possible to establish a single prognostic threshold for the number of CAs in all malignancies, a specific consensus prognostic cut-off must be defined for each individual disease. In order to standardize current cytogenetic practices and apply a single denomination, we suggest defining a low complex karyotype as having 3 CAs, an intermediate complex karyotype as having 4 CAs, and a highly complex karyotype as having 5 or more CAs.