title: The molecular basis of myeloid malignancies.
abstract: Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis.
authors.affiliation: Division of Cellular Therapy/Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Daichi
authors.initials: D
authors.lastname: Inoue
authors.forename: Naoko
authors.initials: N
authors.lastname: Okochi-Watanabe
authors.forename: Naoko
authors.initials: N
authors.lastname: Kato
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komeno
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Enomoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Doki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Uchida
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagiyama
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Togami
authors.forename: Kimihito C
authors.initials: KC
authors.lastname: Kawabata
authors.forename: Reina
authors.initials: R
authors.lastname: Nagase
authors.forename: Sayuri
authors.initials: S
authors.lastname: Horikawa
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Saika
authors.forename: Tomofusa
authors.initials: T
authors.lastname: Fukuyama
authors.forename: Kumi
authors.initials: K
authors.lastname: Izawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakahara
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism
chemical_list: D016044:Fusion Proteins, bcr-abl