Acute Megakaryocytic Leukemia.

Acute megakaryoblastic leukemia (AMKL) is a rare malignancy affecting megakaryocytes, platelet-producing cells that reside in the bone marrow. Children with Down syndrome (DS) are particularly prone to developing the disease and have a different age of onset, distinct genetic mutations, and better prognosis as compared with individuals without DS who develop the disease. Here, we discuss the contributions of chromosome 21 genes and other genetic mutations to AMKL, the clinical features of the disease, and the differing features of DS- and non-DS-AMKL. Further studies elucidating the role of chromosome 21 genes in this disease may aid our understanding of how they function in other types of leukemia, in which they are frequently mutated or differentially expressed. Although researchers have made many insights into understanding AMKL, much more remains to be learned about its underlying molecular mechanisms.

Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.

Acute megakaryoblastic leukemia (AMKL) represents ∼10% of pediatric acute myeloid leukemia cases and typically affects young children (<3 years of age). It remains plagued with extremely poor treatment outcomes (<40% cure rates), mostly due to primary chemotherapy refractory disease and/or early relapse. Recurrent and mutually exclusive chimeric fusion oncogenes have been detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene rearrangements, most commonly NUP98-KDM5A. Human models of NUP98-KDM5A-driven AMKL capable of faithfully recapitulating the disease have been lacking, and patient samples are rare, further limiting biomarkers and drug discovery. To overcome these impediments, we overexpressed NUP98-KDM5A in human cord blood hematopoietic stem and progenitor cells using a lentiviral-based approach to create physiopathologically relevant disease models. The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions. Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient mice led to multiple subtypes of leukemia, including AMKL, that phenocopy human disease phenotypically and molecularly. The integrative molecular characterization of synthetic and patient NUP98-KDM5A AMKL samples revealed SELP, MPIG6B, and NEO1 as distinctive and novel disease biomarkers. Transcriptomic and proteomic analyses pointed to upregulation of the JAK-STAT signaling pathway in the model AMKL. Both synthetic models and patient-derived xenografts of NUP98-rearranged AMKL showed in vitro therapeutic vulnerability to ruxolitinib, a clinically approved JAK2 inhibitor. Overall, synthetic human AMKL models contribute to defining functional dependencies of rare genotypes of high-fatality pediatric leukemia, which lack effective and rationally designed treatments.

Acute Megakaryoblastic Leukemia Developing as Donor Cell Leukemia after Umbilical Cord Blood Transplantation.

A 64-year-old man with acute myeloid leukemia underwent umbilical cord blood transplantation (UCBT). After 11 months of complete remission (CR) following UCBT, the bone marrow showed 7.5% myeloblasts. CR was obtained after a single course of azacitidine monotherapy, but the myeloblasts gradually increased in the blood. We made a diagnosis of acute megakaryoblastic leukemia derived from donor cell with a fluorescence in situ hybridization (FISH) analysis of the sex chromosomes and an immunophenotypic analysis. Azacitidine was administered again and produced a therapeutic effect of stable disease. This case suggests that azacitidine may be a useful therapy for patients with acute megakaryoblastic leukemia in situations in which intensive chemotherapy and transplantation are not indicated.

Pediatric Acute Megakaryoblastic Leukemia: Multitasking Fusion Proteins and Oncogenic Cooperations.

Pediatric leukemia presents specific clinical and genetic features from adult leukemia but the underpinning mechanisms of transformation are still unclear. Acute megakaryoblastic leukemia (AMKL) is the malignant accumulation of progenitors of the megakaryocyte lineage that normally produce blood platelets. AMKL is diagnosed de novo, in patients showing a poor prognosis, or in Down syndrome (DS) patients with a better prognosis. Recent data show that de novo AMKL is primarily associated with chromosomal alterations leading to the expression of fusions between transcriptional regulators. This review highlights the most recurrent genetic events found in de novo pediatric AMKL patients and, based on recent functional analyses, proposes a mechanism of leukemogenesis common to de novo and DS-AMKL.

Integrated differential transcriptome maps of Acute Megakaryoblastic Leukemia (AMKL) in children with or without Down Syndrome (DS).

BACKGROUND: The incidence of Acute Megakaryoblastic Leukemia (AMKL) is 500-fold higher in children with Down Syndrome (DS) compared with non-DS children, but the relevance of trisomy 21 as a specific background of AMKL in DS is still an open issue. Several Authors have determined gene expression profiles by microarray analysis in DS and/or non-DS AMKL. Due to the rarity of AMKL, these studies were typically limited to a small group of samples. METHODS: We generated integrated quantitative transcriptome maps by systematic meta-analysis from any available gene expression profile dataset related to AMKL in pediatric age. This task has been accomplished using a tool recently described by us for the generation and the analysis of quantitative transcriptome maps, TRAM (Transcriptome Mapper), which allows effective integration of data obtained from different experimenters, experimental platforms and data sources. This allowed us to explore gene expression changes involved in transition from normal megakaryocytes (MK, n=19) to DS (n=43) or non-DS (n=45) AMKL blasts, including the analysis of Transient Myeloproliferative Disorder (TMD, n=20), a pre-leukemia condition. RESULTS: We propose a biological model of the transcriptome depicting progressive changes from MK to TMD and then to DS AMKL. The data indicate the repression of genes involved in MK differentiation, in particular the cluster on chromosome 4 including PF4 (platelet factor 4) and PPBP (pro-platelet basic protein); the gene for the mitogen-activated protein kinase MAP3K10 and the thrombopoietin receptor gene MPL. Moreover, comparing both DS and non-DS AMKL with MK, we identified three potential clinical markers of progression to AMKL: TMEM241 (transmembrane protein 241) was the most over-expressed single gene, while APOC2 (apolipoprotein C-II) and ZNF587B (zinc finger protein 587B) appear to be the most discriminant markers of progression, specifically to DS AMKL. Finally, the chromosome 21 (chr21) genes resulted to be the most over-expressed in DS and non-DS AMKL, as well as in TMD, pointing out a key role of chr21 genes in differentiating AMKL from MK. CONCLUSIONS: Our study presents an integrated original model of the DS AMLK transcriptome, providing the identification of genes relevant for its pathophysiology which can potentially be new clinical markers.

A dysmorphic newborn with petechiae and a 'Big Heart'.

A male fetus was noted to have an isolated pericardial effusion. At birth, he had dysmorphic features of Down syndrome and extensive petechiae. He was diagnosed to have transient myeloproliferative disorder. The large pericardial effusion and TMD spontaneously resolved. At 4 years of age, he was diagnosed with acute megakaryoblastic leukaemia, underwent chemotherapy and achieved complete remission.

Myeloid sarcoma with megakaryoblastic differentiation mimicking a sellar tumor.

Myeloid sarcoma (MS) is a localized extra-medullary tumor mass of immature myeloid cells, arising de novo or related to acute myeloid leukemia, of which it can be a forerunner, a coinciding or late event. Less commonly, MS represents an acute blastic transformation of myelodysplastic syndromes or myeloproliferative neoplasms. This rare condition commonly consists of a proliferation of more or less immature cells with a myeloid immunophenotype, very exceptional cases showing a megakaryoblastic or erythroid differentiation. The most common localization of MS is the skin, lymph node, soft tissues and bones, but CNS involvement is exceedingly rare, with no cases reported in the sellar region. We report a 54-year-old man, affected by myeloproliferative neoplasm, JAK2 V617F-positive of 13 years duration, who acutely presented with a third cranial nerve palsy; neuroradiology documented a space-occupying lesion at the level of the sellar, upper clival and right parasellar regions, that was sub-totally removed with a trans-sphenoidal approach. The histological examination documented a proliferation of large, blastic cells, frequently multinucleated; a diagnosis of MS with megakaryoblastic differentiation, arising in a background of chronic idiopathic myelofibrosis, was suggested by immunohistochemistry, owing to CD42b, CD45, CD61 and LAT (linker for activation of T cells) positivity. In addition, homozygous JAK2 V617F mutation was detected from the myeloid sarcoma specimen. A few weeks after surgery, an acute blastic leukemic transformation occurred and, despite chemotherapy, the patient died 2 months after surgery. To the best of our knowledge, this is the first MS case with megakaryoblastic differentiation arising within the CNS.

Acute megakaryoblastic leukemia in a patient with xeroderma pigmentosum: discussion of pathophysiological, prognostic, and toxicological aspects.

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive inherited disease characterized by extreme sensitivity to sunlight. Normal individuals harboring XPD polymorphisms are at increased risk for developing acute lymphoblastic leukemia and acute myeloid leukemia (AML). CASE REPORT: A 33-year-old male XP patient was diagnosed with acute megakaryoblastic leukemia with a complex karyotype. He received standard induction chemotherapy with cytarabine and daunorubicin. After the first cycle of chemotherapy, persistence of blasts was seen and a re-induction cycle with cytarabine, fludarabine, and idarubicin was administered resulting in complete remission. Due to the high-risk profile of his AML, allogeneic stem cell transplantation (SCT) was performed. Following a conditioning regimen with busulfan and cyclophosphamide, the patient received a matched related SCT from his HLA-identical sister. Despite the existence of his DNA repair gene mutation, chemotherapy was normally tolerated by the patient. Unfortunately, he died due to severe sepsis and relapse of AML 45 days after SCT. CONCLUSION: The XPD mutation in our patient may have contributed to the emergence of his high-risk AML. Despite the existence of a DNA repair gene mutation, our XP patient could be treated with full doses of AML-type chemotherapy including allogeneic SCT without encountering unusual toxicity.

Prominent megakaryocytic dysplasia after regression of transient abnormal myelopoiesis associated with GATA-1 mutation.

About a quarter of children with Down syndrome and transient abnormal myelopoiesis (TAM) progress to acute megakaryoblastic leukemia (AMKL). We describe isolated dysmegakaryopoiesis despite complete resolution of TAM in an 18-month-old girl, who developed AMKL 6 months later.

Acute leukemias in children with Down syndrome.

Children with Down syndrome (DS) often present with hematopoietic abnormalities, and are at increased risk of developing leukemia. Specifically, 3-10% of newborns with DS are diagnosed with transient myeloproliferative disease, and children with DS are 500 times more likely to develop acute megakaryoblastic leukemia (AMKL) and 20 times more likely to develop acute lymphoblastic leukemia (ALL) than typical children. This review examines the characteristics of these leukemias and their development in the unique genetic background of trisomy 21. A discussion is also provided for areas of future research and potential therapeutic development.

Identification of TRIB1 R107L gain-of-function mutation in human acute megakaryocytic leukemia.

Trib1 has been identified as a myeloid oncogene in a murine leukemia model. Here we identified a TRIB1 somatic mutation in a human case of Down syndrome-related acute megakaryocytic leukemia. The mutation was observed at well-conserved arginine 107 residue in the pseudokinase domain. This R107L mutation remained in leukocytes of the remission stage in which GATA1 mutation disappeared, suggesting the TRIB1 mutation is an earlier genetic event in leukemogenesis. The bone marrow transfer experiment showed that acute myeloid leukemia development was accelerated by transducing murine bone marrow cells with the R107L mutant in which enhancement of ERK phosphorylation and C/EBPα degradation by Trib1 expression was even greater than in those expressing wild-type. These results suggest that TRIB1 may be a novel important oncogene for Down syndrome-related acute megakaryocytic leukemia.

Development of acute megakaryoblastic leukemia with isochromosome (12p) after a primary mediastinal germ cell tumor in Korea.

The association of hematological malignancies with a mediastinal germ cell tumor (GCT) is very rare. We report one case of a young adult male with primary mediastinal GCT who subsequently developed acute megakaryoblastic leukemia involving isochromosome (12p). A 25-yr-old man had been diagnosed with a mediastinal GCT and underwent surgical resection and adjuvant chemotherapy. At 1 week after the last cycle of chemotherapy, his peripheral blood showed leukocytosis with blasts. A bone marrow study confirmed the acute megakaryoblastic leukemia. A cytogenetic study revealed a complex karyotype with i(12p). Although additional chemotherapy was administered, the patient could not attain remission and died of septic shock. This case was definitely distinct from therapy-related secondary leukemia in terms of clinical, morphologic, and cytogenetic features. To our knowledge, this is the first case report of a patient with mediastinal GCT subsequently developing acute megakaryoblastic leukemia involving i(12p) in Korea.

Acute megakaryocytic leukemia (AMKL,FAB;M7) with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is characterized by an accumulation of multiple congenital anomalies. Although patients with BWS are known to have a higher incidence of embryonal tumors, there has been no reports associated with acute leukemia. This report describes the case of a patient with BWS who developed Acute Megakaryocytic Leukemia (AMKL,FAB;M7). Because most patients with BWS present gigantism, the therapy-related toxicity of chemotherapy can be a very serious problem. This patient exhibited no therapy-related toxicity after chemotherapy, suggesting that acute leukemia with BWS may not require a reduction in dosage.