Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Background: Little is known about blood lymphocyte subpopulations in children with common (CO) or syndromic (SO) obesity. We aimed to describe the blood lymphocyte profiles of obese children and to search for associations with clinical phenotypes.Methods: Main blood lymphocyte subpopulations were analyzed in 159 children with CO and 34 with SO in a retrospective cohort. Phenotypes included obesity history, body mass index (BMI) Z score, percentage fat mass, and inflammatory parameters. Correlations were performed between phenotypes and circulating lymphocyte profiles.Results: Children with SO had a higher BMI Z score (5.5 & PLUSMN; 1.7 SD) than children with CO (4.7 & PLUSMN; 0.9 SD; p = 0.01). Significant differences were found for lymphocyte counts, including a higher percentage of CD19' B cells (SO = 20.1 & PLUSMN; 6.7 vs. CO = 17.1 & PLUSMN; 6.1%, p = 0.03), despite lower absolute numbers (SO = 0.57 & PLUSMN; 0.20 vs. CO = 0.63 & PLUSMN; 1.9 g/L, p < 0.01). However, no difference in the lymphocyte profile was found between children with SO and those with the most severe CO (BMI Z score & GE; 4.7 SD).Conclusion: Children with SO have altered blood lymphocyte profiles with increased prevalence of CD19' B cells, which is closely linked to the degree of obesity severity and inflammatory markers. & COPY; 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Background:The clinical and biological characteristics of children under two years (infants) with acute myeloid leukemia (AML) are different from those of older children.Aims:We aimed to describe the specific characteristics of this population and the potential factors that influence the prognosis.Methods:We analyzed data concerning 438 children with newly‐diagnosed AML treated in the ELAM02 protocol between March 2005 and December 2011, of which 103 were under two years old at diagnosis. The evaluation criteria were overall survival (OS) and event‐free survival (EFS) of infants versus older children. The clinical and biological features were secondary criteria.Results:Infants presented more frequent extra‐medullary presentation than older children. They had a significantly higher proportion of skin lesions and central nervous system involvement (15% vs 3%, P < 0.0001 and 26% vs 12%, P = 0.0005, respectively). The global incidence of KMT2A rearrangements was nearly 55% for infants versus 11% for older children (P < 0.0001). Median five‐year OS was 70.4% for infants versus 71.4% for older children (P = 0.83). Five‐year EFS was 67% for infants versus 58% for older children (P = 0.27).Summary/Conclusion:Infants with AML represent a cohort of patients with specific clinical and biological features. These remarkable differences had no significant impact on their outcome in the ELAM02 protocol.

Background:Acute erythroid leukemia (AEL) is a subtype of acute myeloid leukemia (AML) characterized by an accumulation of variable proportions of erythroid progenitor cells and myeloblasts. Two subgroups of AEL have been proposed: 1‐pure erythroid leukemia (PEL, AML‐M6b) characterized by an accumulation of > 80% of erythroid progenitors and 2‐AML‐M6a characterized by an accumulation of both myeloid and erythroid progenitors, a group that has now been integrated into myelodysplastic syndrome (MDS) by the 2016 World Health Organization (WHO) classification. Earlier studies indicated that mutations of TP53 and epigenetic modifiers genes (e.g. TET2, DNMT3A) are prevalent alterations in AEL. However, the underlying molecular mechanisms driving the erythroid phenotype remain poorly understood.Aims:The aims of this study were to better characterize the mutational and transcriptional landscape of AEL and to model the functional consequence of these alterations.Methods:We collected AEL patient samples and performed transcriptomic (RNAseq) and genetic (exomes) analyses, on 31 and 11 samples respectively. Candidate alterations were then expressed in mouse erythroid progenitors and hematopoietic stem and progenitor cells (HSPC), in vitro and in in vivo bone marrow (BM) reconstitution assays to obtain functional insights.Results:The genetic landscape grouped patients into at least 3 molecular subgroups: 1‐TP53 mutations (32%), 2‐Epigenetic modifiers (e.g. TET2, DNMT3A) mutations (32%), 3‐Others. Some patients present combinations of mutations that could represent the basis for an erythroid bias. For example, a patient showed TP53 mutation with an out‐of‐frame fusion leading to aberrant EPO overexpression. Another patient presented with a TET2 mutation associated with a GATA1 s mutation previously associated with familial macrocytic anemia and megakaryoblastic leukemia with Down's syndrome. Gene expression signatures indicated that several human AEL samples present with drastic changes in the expression of genes related to GATA1 activity, including ERG, ETO2, SPI1 and SKI. Ectopic expression of these genes through retroviral transduction of mouse erythroblasts led to their immortalization in vitro and, when engrafted thereafter in mice, to leukemia presenting characteristics of AEL. Similarly, purified erythroblasts from a TET2 −/− GATA1 s double transgenic mouse model showed high long‐term proliferation capacity in vitro and subsequent murine AEL. In contrast, transplantation of multipotent progenitors transduced with SKI retrovirus or purified from TET2 −/− GATA1 s double transgenics led to the development of a more myeloid disease, respectively mimicking MDS with erythroid component or more homogeneous myeloid leukemia. Therefore, altered activity of these factors in erythroid progenitors led to pure erythroid phenotypes and to mixed erythroid and myeloid phenotypes upon expression in multipotent progenitors.Summary/Conclusion:We report that, in addition to previously described genetic alterations including TP53 and chromatin regulator mutations, human AEL is also characterized by aberrant expression of several genes interfering with GATA1 including ETS factors, ETO2 and SKI. Modeling their ectopic expression in different murine progenitors suggests that the prevalence of the erythroid phenotype is dependent on the targeted cell type. Together, alterations of the GATA1 transcriptional activity and targeting of different stages of the hematopoietic differentiation may explain the continuum of phenotype between MDS and pure erythroid in human AEL.

The clinical and biological characteristics of children under 2 years (infants) with acute myeloid leukemia (AML) are different from those of older children. We aimed to describe the specific characteristics of this population and the potential factors that influence the prognosis. We analyzed data concerning 438 children with newly-diagnosed AML treated in the ELAM02 protocol between March 2005 and December 2011, of which 103 were under 2 years old at diagnosis. The evaluation criteria were overall survival (OS) and event-free survival (EFS) of infants vs older children. The clinical and biological features were secondary criteria. Infants presented more frequent extra-medullary presentation than older children. They had a significantly higher proportion of skin lesions and central nervous system involvement (15% vs 3%, p < 0.0001 and 26% vs 12%, p = 0.0005, respectively). The global incidence of KMT2A rearrangements was nearly 55% for infants vs 11% for older children (p < 0.0001). Median 5-year OS was 70.4% for infants vs 71.4% for older children (p = 0.83). Five-year EFS was 67% for infants vs 58% for older children (p = 0.27). Infants with AML represent a cohort of patients with specific clinical and biological features. These remarkable differences had no significant impact on their outcome in the ELAM02 protocol.

L’obésité est décrite comme une maladie inflammatoire de bas grade responsable des comorbidités chez l’adulte. Chez l’enfant obèse, le profil inflammatoire est peu connu. Le but de notre travail était de décrire les populations lymphocytaires chez des enfants obèses et de rechercher un lien entre populations lymphocytaires et phénotypes liés à l’obésité. Deux cent-sept enfants (122F, âge 13,1 ± 2,5 ans, Z-score IMC 4,8 ± 0,9 DS, âge de début de l’obésité = 3,5 ± 1,8 ans) ont eu une caractérisation phénotypique (histoire de l’obésité, bilan métabolique) et un phénotypage lymphocytaire sanguin (lymphocytes T totaux [CD3], sous populations lymphocytaires T (CD4/CD8) et lymphocytes B totaux [CD19]). Résultats et analyse statistique Au total, 91 % des enfants avaient au moins une anomalie lymphocytaire par comparaison aux normes pédiatriques (PGen) : CD3 < PGen 9 % (n = 18) et > PGen 28 % (n = 57) ; CD19 < PGen 20 % (n = 42) et > PGen 28 % (n = 59) ; CD4 < PGen 13 % (n = 28) et > PGen 34 % (n = 70) ; CD8 < PGen 47 % (n = 97) et > PGen 12 % (n = 25). La comparaison du phénotype selon 3 groupes (A PGen) a montré que le Zscore IMC était plus élevé pour les groupes de CD19, CD3 et CD8 > PGen (CD19 : 5,2 ± 1,1 DS vs 4,7 ± 1,1 DS p = 0,016 ; CD3 : 5,3 ± 1,1 vs 4,6 ± 1,1 p = 0,0002 ; CD4 : 5,1 ± 1,2 vs 4,7 ± 1,2 p = 0,02). Le HOMA était plus élevé pour les CD19 > PGen (3,3 ± 4,2 vs 2,3 ± 2,1 p = 0,046) ainsi que la CRPus (7,8 ± 5,7 mg/L vs 5,8 ± 5,0 mg/L, p = 0,02) et le fibrinogène (4,2 ± 1,2 g/L vs 3,7 ± 0,7 g/L, p = 0,012). Enfin, le HOMA était également plus élevé en cas de CD3 > PGen (3,4 ± 4,4, vs 2,4 ± 1,9 p = 0,04). Il existe des anomalies du phénotype lymphocytaire chez l’enfant obèse avec une relation entre populations lymphocytaires et sévérité du phénotype. Ces résultats sont en faveur de l’existence de remaniements inflammatoires dès l’enfance.

L’exploration d’une thrombopénie prolongée est une situation classique en pédiatrie. La cause la plus fréquente reste le purpura thrombopénique immunologique. Cependant, il est important de savoir remettre en cause ce diagnostic en cas d’atypie, d’association syndromique, d’antécédents familiaux de thrombopénie ou d’hémopathie myéloïde maligne, ou d’évolution inhabituelle, et d’évoquer l’hypothèse d’une thrombopénie constitutionnelle. Il s’agit d’un vaste groupe de pathologies qui a bénéficié ces dernières années des avancées de la génétique et de la biologie moléculaire. Ceci a permis la description d’un grand nombre d’entités clinicobiologiques formant un large spectre de pathologies aux pronostics et aux profils évolutifs diverses. Améliorer les connaissances sur ces pathologies, pour certaines de description récente, a pour but d’adapter au mieux la prise en charge et la surveillance des patients. Devant le nombre croissant d’anomalies génétiques décrites, nous proposons une classification des thrombopénies constitutionnelles basées sur deux données simples : le caractère isolé ou syndromique de la thrombopénie et la taille des plaquettes ou le volume plaquettaire moyen, avec une revue de la littérature récente. Notre but est de faciliter une démarche diagnostique rationnelle et ciblée au sein d’un groupe de pathologies en évolution constante. Malgré les progrès spectaculaires des connaissances, la moitié des patients atteints d’une thrombopénie constitutionnelle n’ont pas à ce jour de diagnostic génétique étiologique. Cette proportion sera probablement réduite dans les prochaines années, ce qui permettra d’améliorer la qualité de la prise en charge des patients.

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

La drépanocytose pose un problème de santé publique au Sénégal. Elle concerne principalement les enfants et les adolescents. L’objectif de notre travail était de déterminer les profils épidémiologiques, cliniques et hématologiques de la drépanocytose homozygote SS dans une cohorte d’enfants suivis à l’hôpital de la paix de Ziguinchor.Il s’agit d’une étude rétrospective portant sur des dossiers d’enfants drépanocytaires. Étaient inclus dans l’étude, les enfants drépanocytaires SS âgés entre deux mois et 21 ans, reçus en phase intercritique durant la période allant du 1er janvier 2015 au 31 août 2017. La phase intercritique était définie par l’absence de fièvre, de douleur osseuse ou abdominale et d’hémolyse aiguë. N’étaient pas inclus dans l’étude les hétérozygotes composites (SC, S bêta-thalassémie). Les paramètres étudiés étaient les données sociodémographiques, épidémiologiques, cliniques et hématologiques.Nous avons colligé 46 (20 filles et 26 garçons) dossiers d’enfants drépanocytaires SS. L’âge moyen des enfants était de huit ans [11 mois–21 ans]. Environ un tiers des enfants avaient un âge supérieur ou égal à cinq ans. L’âge moyen des enfants à la première crise était de 35,5 mois [7–192 mois]. Plus de un tiers des enfants avaient fait une première crise avant le deuxième anniversaire. Le type de la première crise, était dominé par la crise vaso-occlusive (32,6 %) suivi du syndrome pied-main (30,4 %). Les signes cliniques en phase intercritique étaient la pâleur 95,6 %), l’ictère (36,9 %) et la splénomégalie (21,7 %). À l’hémogramme, le nombre de globules blancs moyen était de 12 465 leucocytes/mm3 [5340–26 900]. L’hyperleucocytose, supérieure à 10 000 leucocytes/mm3, était retrouvée chez 34 malades (soit 73,9 %). La totalité des malades présentait une anémie avec une moyenne de 8,6 g/dL [05,7–11,8]. Le taux d’hémoglobine S variait entre 54,6 % et 98,4 %.Le diagnostic et la prise en charge médicale de la drépanocytose SS sont tardifs à Ziguinchor. Le dépistage néonatal pourrait améliorer le diagnostic et favoriser une prise en charge précoce dans la région.Sickle-cell anemia is a public health problem in Senegal. It mainly concerns children and adolescents. The objective of our work was to determine the epidemiological, clinical and hematological profiles of SS homozygous sickle-cell anemia in a cohort of children attending the Ziguinchor Peace Hospital.This is a retrospective study of cases of sickle-cell children. Included in the study were SS sickle-cell children between two months and 21 years of age, who received intercritical treatment during the period starting 1 January 2015 to 31 August 2017. The intercritical phase was defined by the absence of fever, bone or abdominal pain and acute haemolysis. Composite heterozygotes (SC, S beta-thalassemia) were not included in the study. The parameters studied were sociodemographic, epidemiological, clinical and haematological data.We collected 46 (20 girls and 26 boys) S sickle-cell children records. The average age of the children was eight years [11 months–21 years]. Approximately one third of children were ≤ 5 years of age. The average age of children at the first crisis was 35.5 months [7–192 months]. More than one third of the children had had a first crisis before the second birthday. The type of the first crisis experienced by the child was dominated by the vaso-occlusive crisis (32.6%) followed by the foot-hand syndrome (30.4%). Clinical signs in the intercritical phase were pallor (95.6%), jaundice (36.9%) and splenomegaly (21.7%). The hemogram shows a mean white blood cell count of 12,465 leucocyte/mm3 [5340–26,900]. Leukocytosis, greater than 10,000 leucocytes/mm3 was found in 34 patients (73.9%). All patients had anemia with an average of 8.6 g/dL [5.7–11.8]. The hemoglobin S ranged between 54.6 and 98.4%.The diagnosis and medical management of SS sickle-cell disease are late in Ziguinchor. Neonatal screening could improve diagnosis and promote early management in the region.

The most common diagnosis for pediatric thrombocytopenia is immune thrombocytopenia. Nevertheless, in atypical cases, the hypothesis of an inherited thrombocytopenia has to be investigated. We report a series of cases of a newly described entity, genetic thrombocytopenia with mutation in the ankyrine 26 gene, diagnosed from the exploration of five pediatric cases of thrombocytopenia. This entity is characterized by a moderate thrombocytopenia with normal mean platelet volume, and poorly bleeding. Its transmission is autosomal dominant. Final diagnosis is made by sequencing of a short DNA region of ANKRD26 gene. This pathology can be considered as an hematological malignancy predisposition syndrome.

Dix ans après l’introduction du bévacizumab pour la prise en charge des cancers colorectaux, les résultats de l’étude ML18147 et de l’étude CORRECT ont récemment établi qu’il était possible de cibler l’angiogenèse chez des patients ayant été exposés au préalable à un traitement anti-VEGF. L’absence de biomarqueurs validés ne permet pas à ce jour de hiérarchiser les différentes options thérapeutiques. Il semble important de comprendre comment les constats établis à partir des études précliniques et cliniques génèrent des enseignements utiles pour l’optimisation des traitements anti-angiogéniques dans cette indication. Les premières études cliniques ont montré que l’association d’anticorps monoclonaux neutralisant le VEGFA avec la chimiothérapie permettait l’amélioration de la survie des patients porteurs de métastases de cancers colorectaux (AVF2107 et ECOG 3200). Le bénéfice des anti-VEGFA (bévacizumab) dans de telles associations est démontré actuellement avec l’irinotécan, l’oxaliplatine, ou avec le 5-fluorouracile en monothérapie. À ce jour, de tels résultats n’ont pas pu être reproduits avec des inhibiteurs de tyrosine kinase anti-angiogéniques, ces derniers semblant augmenter les effets secondaires liés à la chimiothérapie. Deux études randomisées (AVANT, NSABPC08) semblent démontrer l’absence d’efficacité du bévacizumab sur la maladie micro-métastatique, incitant à prescrire les anti-angiogéniques pour des maladies non résécables. Pour ces patients, le maintien du blocage du VEGFA en deuxième ligne au-delà de la progression de la maladie permet un gain de survie globale. Enfin, le ciblage du VEGFR2 ou de Tie2 permet également d’envisager la prescription d’anti-angiogéniques au-delà de la première ligne métastatique. En effet, les résultats obtenus par les études CORRECT et CONCUR ont démontré un bénéfice du régorafénib dans un contexte de maladies préalablement exposées à l’ensemble des chimiothérapies conventionnelles et au bévacizumab, suggérant l’absence de résistance croisée des anti-angiogéniques avec la chimiothérapie. Cette synthèse expose l’état des lieux des connaissances acquises sur la place des anti-angiogéniques dans la stratégie de traitement des cancers colorectaux, et discute de l’intérêt de leur entretien après chimiothérapie, ainsi que des interrogations soulevées par ces nouvelles stratégies. Les programmes de recherche en cours devront promouvoir le développement de biomarqueurs, afin de permettre la stratification des différentes stratégies thérapeutiques.Ten years after the approval of bevacizumab in colorectal cancer patients, results from ML18147 and CORRECT studies have recently demonstrated the possibility to target angiogenesis in patients previously exposed to anti-VEGF. An increasing number of anti-angiogenic treatments are now available, however, no biomarker has yet succeeded in rationalizing our therapeutic strategies. Nevertheless, several lessons have been learned from preclinical and pivotal clinical studies. The first clinical trials demonstrated a survival benefit, adding VEGFA targeting monoclonal antibodies to chemotherapy in metastatic colorectal cancer patients (AVF2107, ECOG 3200). Many phase III clinical trials confirmed the interest of this strategy, in combination with chemotherapies containing irinotecan, oxaliplatin, or with 5-fluorouracil in monotherapy. To date, such results have not been reproduced with tyrosine kinase inhibitors targeting the angiogenesis pathways, with an increasing rate of chemotherapy related toxicities. Clinical trials performed in the adjuvant setting (AVANT, NSABPC08) failed to demonstrate any efficacy of the anti-VEGFA treatments on the micrometastatic disease, encouraging its prescription in the unresectable cases. On the other hand, a continuous inhibition of angiogenesis during the course of the metastatic disease was shown to be feasible and to extend colon cancer patient's survival in two recent randomized trials. For these patients, the continuation of bevacizumab beyond progression in first line improves overall survival. Lastly, results achieved by the CORRECT and CONCUR studies demonstrated that anti-angiogenics might be effective in colorectal cancers resistant to chemotherapy. This review presents the main results of preclinical and clinical studies sustaining the prescription of anti-angiogenics in metastatic colorectal cancers. The future challenge is to promote the development of biomarkers to enable the stratification of the different therapeutic strategies.

Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.

L’exploration d’une thrombopénie prolongée est une situation classique en pédiatrie. La cause la plus fréquente reste le purpura thrombopénique immunologique. Cependant, il est important de savoir remettre en cause ce diagnostic en cas d’atypie, d’association syndromique, d’antécédents familiaux de thrombopénie ou d’hémopathie myéloïde maligne, ou d’évolution inhabituelle, et d’évoquer l’hypothèse d’une thrombopénie constitutionnelle. Il s’agit d’un vaste groupe de pathologies qui a bénéficié ces dernières années des avancées de la génétique et de la biologie moléculaire. Ceci a permis la description d’un grand nombre d’entités clinico-biologiques formant un large spectre de pathologies aux pronostics et aux profils évolutifs diverses. Améliorer les connaissances sur ces pathologies, pour certaines de description récente, a pour but d’adapter au mieux la prise en charge et la surveillance des patients. Devant le nombre croissant d’anomalies génétiques décrites, nous proposons une classification des thrombopénies constitutionnelles basées sur deux données simples : le caractère isolé ou syndromique de la thrombopénie et la taille des plaquettes ou le volume plaquettaire moyen, avec une revue de la littérature récente. Notre but est de faciliter une démarche diagnostique rationnelle et ciblée au sein d’un groupe de pathologies en évolution constante. Malgré les progrès spectaculaires des connaissances, la moitié des patients atteints d’une thrombopénie constitutionnelle n’ont pas à ce jour de diagnostic génétique étiologique. Cette proportion sera probablement réduite dans les prochaines années, ce qui permettra d’améliorer la qualité de la prise en charge des patients.

Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10; 22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions.