Details

Autor(en) / Beteiligte

• Sato, Tomohiko
• Yoshida, Kenichi
• Toki, Tsutomu
• Kanezaki, Rika
• Terui, Kiminori
• Saiki, Ryunosuke
• Ojima, Masami
• Ochi, Yotaro
• Mizuno, Seiya
• Yoshihara, Masaharu
• Uechi, Tamayo
• Kenmochi, Naoya
• Tanaka, Shiro
• Matsubayashi, Jun
• Kisai, Kenta
• Kudo, Ko
• Yuzawa, Kentaro
• Takahashi, Yuka
• Tanaka, Tatsuhiko
• Yamamoto, Yohei
• Kobayashi, Akie
• Kamio, Takuya
• Sasaki, Shinya
• Shiraishi, Yuichi
• Chiba, Kenichi
• Tanaka, Hiroko
• Muramatsu, Hideki
• Hama, Asahito
• Hasegawa, Daisuke
• Sato, Atsushi
• Koh, Katsuyoshi
• Karakawa, Shuhei
• Kobayashi, Masao
• Hara, Junichi
• Taneyama, Yuichi
• Imai, Chihaya
• Hasegawa, Daiichiro
• Fujita, Naoto
• Yoshitomi, Masahiro
• Iwamoto, Shotaro
• Yamato, Genki
• Saida, Satoshi
• Kiyokawa, Nobutaka
• Deguchi, Takao
• Ito, Masafumi
• Matsuo, Hidemasa
• Adachi, Souichi
• Hayashi, Yasuhide
• Taga, Takashi
• Saito, Akiko M.
• Horibe, Keizo
• Watanabe, Kenichiro
• Tomizawa, Daisuke
• Miyano, Satoru
• Takahashi, Satoru
• Ogawa, Seishi
• Ito, Etsuro

Titel

Landscape of driver mutations and their clinical effects on Down syndrome–related myeloid neoplasms

Ist Teil von

• Blood, 2024-06, Vol.143 (25), p.2627-2643

Erscheinungsjahr

2024

Beschreibungen/Notizen

• Abstract Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.