Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a NUP98-KDM5A or a KMT2A-MLLT6 fusion, and the remaining harbored a CBFA2T3-GLIS2 fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic GATA1 mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.

Lalonde E ，Rentas S ，Wertheim G ，Cao K ，Surrey LF ，Lin F ，Zhao X ，Obstfeld A ，Aplenc R ，Luo M ，Li MM ... -  《-》

The landscape of somatic mutations in Down syndrome-related myeloid disorders.

Yoshida K ，Toki T ，Okuno Y ，Kanezaki R ，Shiraishi Y ，Sato-Otsubo A ，Sanada M ，Park MJ ，Terui K ，Suzuki H ，Kon A ，Nagata Y ，Sato Y ，Wang R ，Shiba N ，Chiba K ，Tanaka H ，Hama A ，Muramatsu H ，Hasegawa D ，Nakamura K ，Kanegane H ，Tsukamoto K ，Adachi S ，Kawakami K ，Kato K ，Nishimura R ，Izraeli S ，Hayashi Y ，Miyano S ，Kojima S ，Ito E ，Ogawa S ... -  《-》

Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome.

Pediatric acute megakaryoblastic leukemia in non-Down syndrome (AMKL) is a unique subtype of acute myeloid leukemia (AML). Novel CBFA2T3-GLIS2 and NUP98-KDM5A fusions recurrently found in AMKL were recently reported as poor prognostic factors. However, their detailed clinical and molecular characteristics in patients treated with recent improved therapies remain uncertain. We analyzed molecular features of 44 AMKL patients treated on two recent Japanese AML protocols, the AML99 and AML-05 trials. We identified CBFA2T3-GLIS2, NUP98-KDM5A, RBM15-MKL1, and KMT2A rearrangements in 12 (27%), 4 (9%), 2 (5%), and 3 (7%) patients, respectively. Among 459 other AML patients, NUP98-KDM5A was identified in 3 patients, whereas CBFA2T3-GLIS2 and RBM15-MKL1 were only present in AMKL. GATA1 mutations were found in 5 patients (11%). Four-year overall survival (OS) and event-free survival (EFS) rates of CBFA2T3-GLIS2-positive patients in AMKL were 41.7% and 16.7%, respectively. Three-year cumulative incidence of relapse in CBFA2T3-GLIS2-positive patients was significantly higher than that of CBFA2T3-GLIS2-negative patients (75.0% vs. 35.7%, P = 0.024). In multivariate analyses, CBFA2T3-GLIS2 was an independent poor prognostic factor for OS (HR, 4.34; 95% CI, 1.31-14.38) and EFS (HR, 2.95; 95% CI, 1.20-7.23). Furthermore, seven (54%) of 13 infant AMKL patients were CBFA2T3-GLIS2-positive. Notably, out of 7 CBFA2T3-GLIS2-positive infants, six (86%) relapsed and five (71%) died. Moreover, all of CBFA2T3-GLIS2-positive patients who experienced induction failure (n = 3) were infants, indicating worse prognosis of CBFA2T3-GLIS2-positive infants. These findings indicated the significance of CBFA2T3-GLIS2 as a poor prognostic factor in AMKL patients, particularly in infants.

Hara Y ，Shiba N ，Ohki K ，Tabuchi K ，Yamato G ，Park MJ ，Tomizawa D ，Kinoshita A ，Shimada A ，Arakawa H ，Saito AM ，Kiyokawa N ，Tawa A ，Horibe K ，Taga T ，Adachi S ，Taki T ，Hayashi Y ... -  《-》

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.

de Rooij JD ，Branstetter C ，Ma J ，Li Y ，Walsh MP ，Cheng J ，Obulkasim A ，Dang J ，Easton J ，Verboon LJ ，Mulder HL ，Zimmermann M ，Koss C ，Gupta P ，Edmonson M ，Rusch M ，Lim JY ，Reinhardt K ，Pigazzi M ，Song G ，Yeoh AE ，Shih LY ，Liang DC ，Halene S ，Krause DS ，Zhang J ，Downing JR ，Locatelli F ，Reinhardt D ，van den Heuvel-Eibrink MM ，Zwaan CM ，Fornerod M ，Gruber TA ... -  《-》

Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21.

Rainis L ，Bercovich D ，Strehl S ，Teigler-Schlegel A ，Stark B ，Trka J ，Amariglio N ，Biondi A ，Muler I ，Rechavi G ，Kempski H ，Haas OA ，Izraeli S ... -  《BLOOD》