El paradigma de la irradiación corporal total en la leucemia linfoblástica aguda: efectividad terapéutica frente a los desafíos de toxicidad / The paradigm of total body irradiation in acute lymphoblastic leukemia: Therapeutic effectiveness against the challenges of toxicity

Introducción: La irradiación corporal total (ICT) forma parte del acondicionamiento mieloablativo del trasplante de progenitores hematopoyéticos (TPH) en hemopatías malignas. Esta terapia ha demostrado recientemente mayor supervivencia en leucemia linfoblástica aguda (LLA) frente a regímenes basados en quimioterapia. Sin embargo, los efectos secundarios son una limitación importante, especialmente en la población pediátrica.Pacientes y métodosAnalizamos retrospectivamente la supervivencia de pacientes con LLA que recibieron un TPH en un hospital terciario entre los años 1996 a 2009 (N=69 TPH en 57 pacientes). Diferenciamos una cohorte que había recibido ICT (N=44) y otra que no (N=25). Posteriormente entrevistamos a los supervivientes del grupo ICT con un mínimo de 10 años de seguimiento (N=18), preguntando acerca de la presencia de efectos secundarios.ResultadosLa supervivencia global (SG) a los 2 y 5 años fue del 79,1 y 65,2%, respectivamente para el grupo ICT y del 66,2 y 55,8% para el grupo no ICT, aunque esta diferencia no fue significativa (p=0,31). La supervivencia libre de evento (SLE) a los 2 y 5 años fue del 77,3 y 63,6%, respectivamente para el grupo ICT y del 56 y 32% para el grupo no ICT (p=0,02). La probabilidad de recidiva (PR) a los 2 años habiendo recibido ICT fue del 10% y sin haber recibido ICT del 28,6% (p=0,005). Los supervivientes que recibieron ICT desarrollaron neoplasias secundarias (39%), dislipemia (67%), alteraciones cognitivas (44%), infecciones respiratorias de repetición (39%), alteraciones tiroideas (45%), insuficiencia ovárica precoz (89%), cataratas (22%) y problemas psicológicos (44%), aunque la calidad de vida, valorada por ellos mismos, fue considerada como buena para el 83% de los encuestados.ConclusionesLos pacientes que recibieron ICT tuvieron significativamente mayor SLE y menor PR. Sin embargo, los efectos adversos son frecuentes e importantes, aunque no afectan subjetivamente a la calidad de vida. (AU)

Introduction: Total body irradiation (TBI) is part of the myeloablative conditioning for hematopoietic stem cell transplantation (HSCT) in malignant hematologic disorders. This therapy has recently shown improved survival in acute lymphoblastic leukemia (ALL) compared to chemotherapy-based regimens. However, side effects are a significant limitation, especially in the pediatric population.Patients and methodsWe retrospectively analyzed the survival of patients with ALL who underwent an HSCT at a tertiary hospital between 1996 and 2009 (N=69 HSCT in 57 patients). We differentiated a cohort that received TBI (N=44) from another that did not (N=25). Subsequently, we interviewed the survivors from the TBI group with a minimum of 10 years of follow-up (N=18), asking about the presence of side effects.ResultsThe overall survival (OS) at 2 and 5 years was 79.1% and 65.2% respectively for the TBI group and 66.2% and 55.8% for the non-TBI group, although this difference was not significant (P=.31). The event-free survival (EFS) at 2 and 5 years was 77.3% and 63.6% respectively for the TBI group and 56% and 32% for the non-TBI group (P=.02). The probability of relapse (PR) at 2 years for those who received TBI was 10% compared to 28.6% for those who did not receive TBI (P=.005). Survivors who received TBI developed secondary neoplasms (39%), dyslipidemia (67%), cognitive impairments affecting memory (44%), recurrent respiratory infections (39%), thyroid abnormalities (45%), premature ovarian failure (89%), cataracts (22%), and psychological problems (44%). However, the quality of life, as self-assessed by the patients, was considered good for 83% of the participants.ConclusionsPatients who received TBI had significantly higher EFS and lower PR. However, adverse effects are frequent and significant, although they do not subjectively affect quality of life. (AU)

First report of familial mixed phenotype acute leukemia: shared clinical characteristics, Philadelphia translocation, and germline variants.

While our understanding of the molecular basis of mixed phenotype acute leukemia (MPAL) has progressed over the decades, our knowledge is limited and the prognosis remains poor. Investigating cases of familial leukemia can provide insights into the role of genetic and environmental factors in leukemogenesis. Although familial cases and associated mutations have been identified in some leukemias, familial occurrence of MPAL has never been reported. Here, we report the first cases of MPAL in a family. A 68-year-old woman was diagnosed with MPAL and received haploidentical stem cell transplantation from her 44-year-old son. In four years, the son himself developed MPAL. Both cases exhibited similar characteristics such as biphenotypic leukemia with B/myeloid cell antigens, Philadelphia translocation (BCR-ABL1 mutation), and response to acute lymphoblastic leukemia-type chemotherapy. These similarities suggest the presence of hereditary factors contributing to the development of MPAL. Targeted sequencing identified shared germline variants in these cases; however, in silico analyses did not strongly support their pathogenicity. Intriguingly, when the son developed MPAL, the mother did not develop donor-derived leukemia and remained in remission. Our cases provide valuable insights to guide future research on familial MPAL.

Clinico-hematological and immunophenotypic profile of acute leukemia of ambiguous lineage: A four year experience from a single tertiary care centre of West India.

Background: : Acute leukemia of ambiguous lineage (ALAL) is a heterogeneous group of rare leukemias that lacks definite evidence of differentiation along one lineage. It includes acute undifferentiated leukemia and mixed-phenotype acute Leukaemia (MPAL). Aims: The present study highlighted the clinicohematological and immunophenotypic profile of ALAL cases diagnosed in the tertiary care centre of western India. Study Design: Retrospective observational study. Methods and Materials: Patients diagnosed with acute leukemia, preferably their bone marrow aspirate samples, were collected in ethylene diamine tetra-acetic acid-vial. The immunophenotypic study was done using the Fluorescence Activated Cell Sorting (FACS) Canto Eight color flow cytometer and a broad panel of monoclonal antibodies. The patients were diagnosed for ALAL, based on the World Health Organization (WHO) 2017 classification. Statistical Analysis Used: Descriptive statistics with categorical and continuous variables. Results: Overall incidence of ALAL was about 2.1%, and singly MPAL and AUL were 1.8%, and 0.3%, in frequency, respectively. The age range was 4 to 57 (median age 21 years), of which 11 (57.9%) were adults and eight were children (42.1%). There was male predominance with Male: Female ratio of 5.3:1. On immunophenotyping, B/myeloid MPAL (42.1%) was the commonest among the ALAL. Translocation t(9;22) was the most common cytogenetic abnormality found mainly in B/myeloid MPAL. Two cases were of chronic myeloid leukemia in a mixed phenotypic blast crisis. Over all prognosis of ALAL was poor. Conclusion: ALAL is overall associated with poor prognosis as both their diagnosis and treatment decisions are difficult owing to the lack of optimum treatment data and the rarity of the disease. Hence, A careful diagnosis with the help of immunophenotyping is crucial.

A Case of Acute Mixed Cell Leukemia Resembling AML1-ETO Positive Acute Myeloid Leukemia.

BACKGROUND: The aim of the study was to improve the understanding of complex karyotype acute mixed cell leukemia containing pseudo Chediak-Higashi granules. METHODS: A case of acute mixed cell leukemia resembling AML1-ETO positive acute myeloid leukemia was reported. The results of morphological, immunophenotypic, and cytogenetic tests were analyzed by reviewing relevant literature. RESULTS: The patient was a young boy with clinical manifestations of recurrent fever. Bone marrow smear: Granulocyte system hyperplasia is obvious, visible at each stage, primitive cells account for 12%. These cells are large in volume, mostly round or class round, with abundant cell mass, stained gray blue, unbalanced development of some nuclear plasma, abnormal cytoplasmic staining, and visible "sunrise red" -like changes. Typical Auer bodies, pseudo Chadiak-Higashi granules and phagocytic erythroid substances were observed. The nuclei are irregular in shape, distorted and depressed, with fine chromatin and prominent large nucleoli. Bone marrow was extracted 3 days later, the bone marrow smear showed 65% primitive cells. The morphology of primitive cells was similar to that of 3 days ago. The results of flow cytometry showed that the primary/naive T cells in the samples possessed nuclear cells. Flow cytometry showed two groups of abnormal cells. One group accounted for 3.87% of nuclear cells and was a primitive/naive T-cell phenotype, mainly expressing: CD34+, CD7+, CD5+, CD2dim+, MPO-, CCD3 + part, CD3-, CD4-, CD8 -, CD117 -, CD13-, CD33-, HLA - DR -, CD10-, CD11b-, CD56-. The other group which accounted for 79.8% of the nuclear cells was monocyte phenotype, mainly expressing: CD34-, CD117-, CD13+ small amount, CD33+, HLA-DR-, CD11b+, CD14+, CD15+, CD36+, CD56+, CD64+, CD4+, CD85J+, CD85K + part. It matched the immunophenotype of acute mixed cell leukemia (T/MMPAL). Immunophenotypic leukemia-related fusion genes were negative, and karyotype analysis results were 45, XY, T (11; 12)(p13; Q13), -12-17, + mar [12]/90 < n > 4, idem x 2 [6]/46, XY. Combined with the above results, acute mixed cell leukemia was diagnosed. CONCLUSIONS: The flow cytometry is the gold standard in the diagnosis of acute mixed cell leukemia. The diagnosis of acute mixed cell leukemia requires the combination of clinical manifestations, cellular morphology, immunology, cytogenetics and molecular biology, and the comprehensive diagnosis efficiency is obviously better than that of morphology.

B- and T-cell acute lymphoblastic leukemias evade chemotherapy at distinct sites in the bone marrow.

Persistence of residual disease after induction chemotherapy is a strong predictor of relapse in acute lymphoblastic leukemia (ALL). The bone marrow microenvironment may support escape from treatment. Using three-dimensional fluorescence imaging of ten primary ALL xenografts we identified sites of predilection in the bone marrow for resistance to induction with dexamethasone, vincristine and doxorubicin. We detected B-cell precursor ALL cells predominantly in the perisinusoidal space at early engraftment and after chemotherapy. The spatial distribution of T-ALL cells was more widespread with contacts to endosteum, nestin+ pericytes and sinusoids. Dispersion of T-ALL cells in the bone marrow increased under chemotherapeutic pressure. A subset of slowly dividing ALL cells was transiently detected upon shortterm chemotherapy, but not at residual disease after chemotherapy, challenging the notion that ALL cells escape treatment by direct induction of a dormant state in the niche. These lineage-dependent differences point to niche interactions that may be more specifically exploitable to improve treatment.

Eficacia y seguridad de uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma philadelphia negativo en recidiva o refractaria / Efficacy and safety of pediatric use of blinatumomab, for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia with Philadelphia chromosome negative

ANTECEDENTES: El presente dictamen ha sido elaborado en el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, la cual fue aprobada mediante la Resolución N° 111-IETSI-ESSALUD-2021 del Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Bajo dicho contexto, el presente documento expone la evaluación de la eficacia y seguridad del uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma Philadelphia negativo en recidiva o refractaria. ASPECTOS GENERALES: La leucemia linfoblástica aguda (LLA) es la neoplasia hematológica más frecuente de la etapa infantil, potencialmente curable hasta en un 90 % de los casos (Hunger y Mullighan 2015). En Perú, se ha estimado una incidencia esperada de 270 a 360 casos nuevos de LLA por año en niños menores de 14 años (Castro-Arechaga et al. 2018). La LLA se clasifica, según la Organización Mundial de la Salud, en LLA de células B, LLA de células T y leucemia de células de Burkitt, tomando en cuenta la morfología y perfil citogenético de los blastos leucémicos (Terwilliger y Abdul-Hay 2017). La LLA de células B es la forma más común de LLA (Inaba y Mullighan 2020). El cromosoma Philadelphia aparece por una translocación recíproca entre los cromosomas 9 y 22 t (9;22) (q34; q11.2), llegando a estar presente en el 3 % al 5 % de los niños con leucemia linfoblástica aguda (Kaczmarska et al. 2021). Además, se ha observado que en los pacientes con LLA que no presentan el cromosoma Philadelphia (cromosoma Philadelphia negativo o Ph-) presentan una tasa de remisión completa de la enfermedad hasta en un 90 % de los casos con una sobrevida global a los 5 años de 43 % (Huguet et al. 2009). METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad del uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma Philadelphia negativo en recidiva o refractaria. Esta búsqueda se realizó utilizando los buscadores: National Library of Medicine (PubMed-MEDLINE), Cochrane Library, LILACS y Web of Science. Adicionalmente, se realizó una búsqueda manual del listado de referencias bibliográficas de los estudios seleccionados a fin de identificar otros estudios que pudieran ser útiles para la presente evaluación. Por otro lado, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como The National Institute for Health and Care Excellence (NICE) y The Canadian Agency for Drugs and Technologies in Health (CADTH). Esta búsqueda se completó revisando publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica y hematológica dentro de América y Europa, como The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), The European Society of Medical Oncology (ESMO), y The British Society for Haematology (BSH). Finalmente, se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. Las estrategias de la búsqueda para identificar la evidencia de ECA se encuentran en las Tabla A, B, C y D del Material Suplementario. La búsqueda de literatura considero GPC, priorizando aquellas que elaboraran recomendaciones basadas en la evidencia; considerando además aquellas guías de referencia para los servicios de oncología y hematología de la institución; ETS; revisiones sistemáticas con metaanálisis de ECA basado en comparaciones directas; y ECA que abordaran la pregunta PICO del presente dictamen. Al no encontrar ECA que ayudara a responder de manera específica la PICO de interés, se pasó a revisar los ensayos pivotales de aprobación de uso del fármaco blinatumomab en la población de interés. Se incluyeron las publicaciones en inglés y español. Se excluyeron estúdios observacionales, series de casos, reportes de casos, cartas al editor, los comentarios, las editoriales, suplementos y los resúmenes de congresos. RESULTADOS: GPC: guía de práctica clínica; ETS: evaluación de tecnologías sanitarias; RS: revisión sistemática; ECA: ensayo clínico aleatorizado; LiLACS: Literatura Latinoamericana y del Caribe en Ciencias de la Salud; BRISA: Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas. Flujograma adaptado de: Page MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. De los 7 artículos que se recuperaron para ser leídos a texto completo (Yu, Wang, y Huang 2019; von Stackelberg et al. 2016; Queudeville y Ebinger 2021; Ponvilawan et al. 2021; Halford et al. 2021; Brown et al. 2021; Locatelli et al. 2021), ninguno aportó información específica para la pregunta PICO. En la búsqueda manual, se encontraron dos guías de práctica clínica: una de NCCN (NCCN 2022) y otra del Comité Canadiense de Revisión de Medicamentos Oncológicos (Pan-Canadian Oncology Drug Review), comité asesor adscrito a CADTH (pCODR-CADTH 2017). Además, se decidió incluir un ensayo de fase 1/fase II (von Stackelberg et al. 2016), al no haber ECA de fase III que respondieran de manera directa la PICO de interés. Este ensayo es el estudio pivotal con el que FDA dio autorización a blinatumomab para el tratamiento de pacientes pediátricos con LLA de precursores de células B en recaída o refractarios (FDA 2018). Asimismo, se incluyó el estudio sin grupo de comparación RIALTO (Locatelli et al. 2022) por ser un ensayo clínico que proporciona información adicional sobre la seguridad de blinatumomab en la población pediátrica. CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma Philadelphia negativo en recidiva o refractaria.

Resultados preliminares tras la instauración del programa con medicamentos CAR-T en leucemia aguda linfoblástica en un centro pediátrico / Building a CAR-T cell therapy program in a pediatric hemato-oncology department. Preliminary data

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How I Diagnose Acute Leukemia of Ambiguous Lineage.

OBJECTIVES: Classification of acute leukemia involves assigning lineage by resemblance to normal progenitor cells. This approach provides descriptive information about the blast cells that is useful for disease monitoring, provides clues to pathogenesis, and can help clinicians select effective chemotherapeutic regimens. Acute leukemias of ambiguous lineage (ALALs) are those leukemias that either fail to show evidence of myeloid, B-, or T-lymphoid lineage commitment or show evidence of commitment to more than 1 lineage. The different treatment regimens for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) make ALAL a challenge both diagnostically and therapeutically. METHODS: Current classification criteria have reduced the reported incidence of mixed-lineage leukemias by emphasizing fewer markers and categorizing some biphenotypic leukemias with recurrent cytogenetic abnormalities as other entities. Several recent studies have explored the genomic and epigenetic landscape of mixed-phenotype acute leukemia (MPAL) and have suggested a further refinement of the World Health Organization classification to emphasize the genomic heterogeneity of MPAL. RESULTS: Genomic and expression profile data for MPAL reveal mutations commonly seen in both AML and ALL, with T-/myeloid MPAL showing overlapping features with early T-cell precursor lymphoblastic leukemia. CONCLUSIONS: Our review aimed to discuss the diagnostic challenges, recent genomic studies, and therapeutic strategies in this poorly understood disease.

Blinatumomabe para leucemia linfoblástica aguda (LLA) B derivada pediátrica em primeira recidiva medular de alto risco / Blinatumomab for pediatric B-derived acute lymphoblastic leukemia (ALL) in first high-risk spinal cord relapse

INTRODUÇÃO: A leucemia linfoblástica aguda (LLA) pediátrica é uma neoplasia maligna agressiva e heterogênea caracterizada pela proliferação clonal e acúmulo de linfoblastos na medula óssea e sangue periférico. Entre os pacientes pediátricos, mais de 95% atingem remissão completa após o primeiro tratamento e 75% a 85% permanecem livre de doença por cinco anos após o diagnóstico. Porcentagens de 15% a 20% sofrem recidiva que são classificadas em risco padrão (RP) ou alto risco (AR). Em crianças com primeira recidiva medular de alto risco a sobrevida global é de 20%. A recidiva após o tratamento inicial é a segunda maior causa de mortalidade relacionada ao câncer em crianças. Crianças que apresentam recidiva de alto risco ao tratamento inicial são candidatas ao transplante de células hematopoiéticas após atingirem uma segunda remissão completa, entretanto, as chances de remissão diminuem significativamente entre a primeira, segunda e terceiras recidivas. Nessa população, a presença de doença residual

Leucemia aguda de fenotipo mixto: presentación de un caso pediátrico de Perú / Acute leukemia of mixed phenotype: presentation of a pediatric case from Peru

Introducción: Las leucemias agudas de linaje ambiguo representan un grupo heterogéneo de leucemias sin una clara diferenciación del linaje celular. Constituyen alrededor de 2 a 5 por ciento del total de leucemias agudas. Objetivo: Describir un caso de leucemia aguda de fenotipo mixto (LAFM) en un paciente pediátrico de 4 años de Lambayeque, Perú. Presentación del caso: Se evaluó una muestra de sangre periférica de un niño de 4 años de edad, cuyo inmunofenotipo por citometría de flujo evidenció una población, correspondiente al 94 por ciento de la celularidad total, de linajes mieloide compatible con diferenciación a linaje neutrófilo y en menor medida a monocítica/célula dendrítica (CD123 intenso), con expresión de mieloperoxidasa (MPO) y CD33 intensos; CD13, CD64 y CD66c parcial; y expresión de marcadores de linaje linfoide B (CD19 y CD22 intensos). Este fenotipo obliga a descartar la t(8;21), y anomalías del gen MLL. Por los mencionados hallazgos, la presente leucemia fue clasificada como leucemia aguda de fenotipo mixto, B/Mieloide. Conclusiones: Se concluyó como una leucemia aguda de fenotipo mixto B/Mieloide, con la peculiar inclinación del linaje mieloide hacia neutrófilos y en menor medida hacia monocítica/célula dendrítica(AU)

Introduction: Acute leukemias of ambiguous lineage represent a heterogeneous group of leukemias without a clear differentiation of the cell lineage. They constitute about 2 to 5 percent of all acute leukemias. Objective: To describe a case of acute leukemia of mixed phenotype (LAFM) in a 4-year-old pediatric patient from Lambayeque, Peru. Case presentation: A peripheral blood sample from a 4-year-old boy was evaluated, whose immunophenotype by flow cytometry showed a population, corresponding to 94 percent of total cellularity, of myeloid lineages compatible with differentiation to neutrophil lineage and in less to monocytic/dendritic cell (CD123 high), with expression of myeloperoxidase (MPO) and CD33 high; CD13, CD64 and CD66c partial; and expression of B lymphoid lineage markers (CD19 and CD22 high). This phenotype requires ruling out the t (8; 21), and abnormalities of the MLL gene. Due to the aforementioned findings, the present leukemia was classified as acute leukemia of mixed phenotype, B/Myeloid. Conclusions: It was concluded as an acute leukemia of mixed phenotype B/Myeloid, with the peculiar inclination of the myeloid lineage towards neutrophils and to a lesser extent towards monocytic/dendritic cell(AU)

LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.

Although great advances have been made in understanding the pathobiology of mixed lineage leukemia-rearranged (MLL-r) leukemias, therapies for this leukemia have remained limited, and clinical outcomes remain bleak. In order to identify novel targets for immunotherapy treatments, we compiled a lineage-independent MLL-r leukemia gene signature using publicly available data sets. Data from large leukemia repositories were filtered through the in silico human surfaceome, providing a list of highly predicted cell surface proteins overexpressed in MLL-r leukemias. LAMP5, a lysosomal associated membrane protein, is expressed highly and specifically in MLL-r leukemia. We found that LAMP5 is a direct target of the oncogenic MLL-fusion protein. LAMP5 depletion significantly inhibited leukemia cell growth in vitro and in vivo. Functional studies showed that LAMP-5 is a novel modulator of innate-immune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-kB signaling and increased activation of type-1 interferon signaling downstream of Toll-like receptor/interleukin 1 receptor activation. These effects were attributable to the critical role of LAMP-5 in transferring the signal flux from interferon signaling endosomes to pro-inflammatory signaling endosomes. Depletion of IRF7 was able to partially rescue the cell growth inhibition upon LAMP5 downregulation. Lastly, LAMP-5 was readily detected on the surface of MLL-r leukemia cells. Targeting surface LAMP-5 using an antibody-drug conjugate leads to significant cell viability decrease specifically in MLL-r leukemias. Overall, based on the limited expression throughout human tissues, we postulate that LAMP-5 could potentially serve as an immunotherapeutic target with a wide therapeutic window to treat MLL-r leukemias.

The Intrinsically Disordered Proteins MLLT3 (AF9) and MLLT1 (ENL) - Multimodal Transcriptional Switches With Roles in Normal Hematopoiesis, MLL Fusion Leukemia, and Kidney Cancer.

AF9 (MLLT3) and ENL (MLLT1) are members of the YEATS family (named after the five proteins first shown to contain this domain: Yaf9, ENL, AF9, Taf14, Sas5) defined by the presence of a YEATS domain. The YEATS domain is an epigenetic reader that binds to acetylated and crotonylated lysines, unlike the bromodomain which can only bind to acetylated lysines. All members of this family have been shown to be components of various complexes with roles in chromatin remodeling, histone modification, histone variant deposition, and transcriptional regulation. MLLT3 is a critical regulator of hematopoiesis with a role in maintaining the hematopoietic stem or progenitor cell (HSPC) population. Approximately 10% of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) patients harbor a translocation involving MLL (mixed lineage leukemia). In the context of MLL fusion patients with AML and ALL, MLL-AF9 and MLL-ENL fusions are observed in 34 and 31% of the patients, respectively. The intrinsically disordered C-terminal domain of MLLT3 (AHD, ANC1 homology domain) undergoes coupled binding and folding upon interaction with partner proteins AF4, DOT1L, BCOR, and CBX8. Backbone dynamics studies of the complexes suggest a role for dynamics in function. Inhibitors of the interaction of the intrinsically disordered AHD with partner proteins have been described, highlighting the feasibility of targeting intrinsically disordered regions. MLLT1 undergoes phase separation to enhance recruitment of the super elongation complex (SEC) and drive transcription. Mutations in MLLT1 observed in Wilms tumor patients enhance phase separation and transcription to drive an aberrant gene expression program.

Use of midostaurin in mixed phenotype acute leukemia with FLT3 mutation: A case series.

Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia where blasts present phenotypes from more than one lineage. A poor prognostic has been associated with this disease, and limited data are currently available to guide the choice of therapy. Regarding FLT3-positive MPAL, only one case treated with midostaurin has been published to date. Here, we report the successful use of midostaurin to treat three FLT3-positive MPAL T/myeloid and B/myeloid patients. Midostaurin was successfully added to intensive induction (two patients) and consolidation chemotherapy (three patients) without significant adverse events requiring a dose adjustment or discontinuation. The therapy received resulted in complete remission for two patients and complete remission with an incomplete hematologic recovery for the third. All patients proceeded to HSCT and stayed in remission after an extended follow-up respectively at 28, 31, and 11 months later. These results suggest that the addition of midostaurin during induction and consolidation therapy may represent a treatment option for FLT3-positive MPAL.

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi-omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi-omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi-omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.

[B-cell acute lymphoblastic leukemia with glycophorin A expression].

This study reports a case of a 49-year-old woman having B-cell acute lymphoblastic leukemia with glycophorin A, a representative erythroid marker, expression. According to the WHO criteria for mixed phenotype acute leukemia (MPAL), erythroid lineage is not defined, and to the best of our knowledge, only one other case with erythroid/B-cell biphenotypic acute leukemia has been reported previously. To establish the disease entity and clarify the pathophysiology of erythroid/lymphoid MPAL, additional cases need to be analyzed.