title: Clonal architecture of chronic myelomonocytic leukemias.
abstract: Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MPN/MDS, have identified common mutations in genes encoding signaling, epigenetic, transcription, and splicing factors. In the present study, we interrogated the clonal architecture by mutation-specific discrimination analysis of single-cell-derived colonies in 28 patients with chronic myelomonocytic leukemias (CMML), the most frequent MPN/MDS. This analysis reveals a linear acquisition of the studied mutations with limited branching through loss of heterozygosity. Serial analysis of untreated and treated samples demonstrates a dynamic architecture on which most current therapeutic approaches have limited effects. The main disease characteristics are early clonal dominance, arising at the CD34(+)/CD38(-) stage of hematopoiesis, and granulomonocytic differentiation skewing of multipotent and common myeloid progenitors. Comparison of clonal expansions of TET2 mutations in MDS, MPN, and CMML, together with functional invalidation of TET2 in sorted progenitors, suggests a causative link between early clonal dominance and skewed granulomonocytic differentiation. Altogether, early clonal dominance may distinguish CMML from other chronic myeloid neoplasms with similar gene mutations.
authors: Inserm UMR1009, Villejuif, France.
authors: Raphaël
authors: R
authors: Itzykson
authors: Olivier
authors: O
authors: Kosmider
authors: Aline
authors: A
authors: Renneville
authors: Margot
authors: M
authors: Morabito
authors: Claude
authors: C
authors: Preudhomme
authors: Céline
authors: C
authors: Berthon
authors: Lionel
authors: L
authors: Adès
authors: Pierre
authors: P
authors: Fenaux
authors: Uwe
authors: U
authors: Platzbecker
authors: Olivier
authors: O
authors: Gagey
authors: Philippe
authors: P
authors: Rameau
authors: Guillaume
authors: G
authors: Meurice
authors: Cédric
authors: C
authors: Oréar
authors: François
authors: F
authors: Delhommeau
authors: Olivier A
authors: OA
authors: Bernard
authors: Michaela
authors: M
authors: Fontenay
authors: William
authors: W
authors: Vainchenker
authors: Nathalie
authors: N
authors: Droin
authors: Eric
authors: E
authors: Solary
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics* / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D059645:Mutation Rate; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology