KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice

Zhao, Ling; Melenhorst, J. Joseph; Alemu, Lemlem; Kirby, Martha; Anderson, Stacie M.; Kench, Maggie; Hoogstraten-Miller, Shelley; Brinster, Lauren R.; Kamikubo, Yasuhiko; Gilliland, D. Gary; Liu, P. Paul

doi:10.1182/blood-2011-02-338210

Cited by 43 publications

(25 citation statements)

References 48 publications

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Section: Cbfb-myh11mentioning

confidence: 61%

“…Recently, mutated KIT was found to cooperate with the CBFB-MYH11 fusion toward leukemogenesis in mice. 38 Our data suggest that this cooperation might be limited to type A fusion transcripts and that other cooperative events occur in inv(16)/t(16;16) AML with non-type A fusions.To gain further biologic insights into the biology of inv(16)/ t(16;16) AML with different fusion types, we performed a microarray analysis to assess differences in the genome-wide gene expression between patients with non-type A and type A fusion transcripts with wild-type KIT. We observed that patients with non-type A fusion showed an up-regulation of genes involved in the activation of caspase activity, cell differentiation and cell cycle control in addition to increased expression of other genes that have been previously linked to myeloid leukemogenesis, including GFI1 or DNMT3B.…”

mentioning

confidence: 61%

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inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations

Schwind

Edwards

Nicolet

et al. 2013

Blood

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• Patients with inv(16) non-typeA CBFB-MYH11 fusions lack KIT mutations and have distinct clinical and cytogenetic features.• inv(16) non-type A fusions have a distinct geneexpression profile with upregulation of genes associated with apoptosis, differentiation, and cell cycle.The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n ‫؍‬ 182; 87%) and non-type A (n ‫؍‬ 26; 13%) patients. At diagnosis, non-type A patients had lower white blood counts (P ‫؍‬ .007), and more often trisomies of chromosomes 8 (P ‫؍‬ .01) and 21 (P < .001) and less often trisomy 22 (P ‫؍‬ .02). No patient with non-type A fusion carried a KIT mutation, whereas 27% of type A patients did (P ‫؍‬ .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non-type A and type A patients with wild-type KIT were similar. We also derived a fusion-type-associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed-among others-an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non-type A patients. We conclude that non-type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile. (Blood. 2013;121(2): 385-391) IntroductionApproximately 5%-7% of acute myeloid leukemia (AML) patients have an inv(16)(p13q22) or t(16;16)(p13;q22) [hereafter referred to as inv(16)/t(16;16)]. [1][2][3] This cytogenetic group is usually associated with high complete remission (CR) rates and a relatively favorable outcome, especially when treated with repetitive cycles of highdose cytarabine as consolidation therapy. 4,5 However, 30%-40% of these patients experience relapse. [6][7][8][9][10] We and others reported that the presence of a KIT mutation confers worse outcome in inv(16)/t(16;16) patients. [10][11][12] Molecularly, inv(16)/t(16;16) results in the juxtaposition of the myosin, heavy chain 11, smooth muscle gene (MYH11) at 16p13 and the core-binding factor, ␤ subunit gene (CBFB) at 16q22, and creation of the CBFB-MYH11 fusion gene. 13,14 Because of the variability of the genomic breakpoints within CBFB and MYH11, more than 10 differently sized CBFB-MYH11 fusion transcript variants have been reported. 15,16 More than 85% of fusions are type A, and 5%-10% each are type D and type E fusions. [15][16][17][18][19][20] Fusion types B, C, and F-K have been reported mostly in single cases. [15][16][17][18][19][20] To our knowledge, only one study examined the biologic and clinical significance of different CBFB-MYH11 fusions, but did not characterize the KIT mutation status. 18 Here, we report the ...

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Section: Cbfb-myh11mentioning

confidence: 61%

mentioning

confidence: 61%

inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations

Schwind

Edwards

Nicolet

et al. 2013

Blood

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“…12,32,33 Thus, inv(16) AML constitutes a paradigm for the model explaining AML leukemogenesis, where second hits causing survival/proliferation advantage (RAS, KIT, or FLT3 mutations) cooperate with a primary hit (CBFB/MYH11 rearrangement) that confers a block in hematopoietic differentiation. 4 This model is supported by animal studies, where the coexpression of Cbfb/MYH11 with mutant KIT 34 or CBFB/MYH11 with FLT3-ITD 35 induced or accelerated the development of leukemia. Although intensive postremission therapy, such as repetitive cycles of higher doses of cytarabine, has substantially improved outcome of patients with inv(16) AML, 15 approximately half of the patients in this cytogenetic AML subgroup are still not cured.…”

Section: Discussionmentioning

confidence: 90%

Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG)

Paschka

Schlenk

et al. 2013

Blood

167

148

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“…50 Recent mice studies provided further evidence for mutant Kit as a sufficient cooperative event in CBF leukemogenesis. [50][51][52] In addition, one study showed that the Kit D814V A-loop mutant (corresponding to human KIT D816V ) and a distinct KIT exon 8 mutant differ with respect to their transforming abilities. 52 In that study, the coexpression of Runx1-Run1xt1 and Kit D814V resulted in lethal hematopoietic malignancies of short-term latency (2-4 months) in all cases including AML (45%), myeloproliferative neoplasia (35%), and pre-B-acute lymphoblastic leukemia (20%), whereas only half of the mice that coexpressed Runx1-Runx1t1 and the Kit exon 8 mutant developed AML with a latency of 4-5 months within the observation time of 1 year; AML was the only malignant hematological phenotype noticed in these animals.…”

Section: Kitmentioning

confidence: 99%

Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation?

Paschka

Döhner

2013

Hematology

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Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered in the setting of repetitive cycles. For many years, high-dose cytarabine was the standard treatment in CBF-AML resulting in favorable long-term outcome in approximately half of the patients. Therefore, CBF-AML patients are generally considered to be a favorable AML group. However, a substantial proportion of patients cannot be cured by the current treatment. Additional genetic alterations discovered in CBF-AML help in our understanding of the process of leukemogenesis and some of them may refine the risk assessment in CBF-AML and, importantly, also serve as targets for novel therapeutic approaches. We discuss the clinical and genetic heterogeneity of CBF-AML, with a particular focus on the role of KIT mutations as a prognosticator, and also discuss recent efforts to target the KIT kinase in the context of existing therapeutic regimens.

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KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice

Abstract: KIT mutations are the most common secondary mutations in inv (16)

Cited by 43 publications

References 48 publications

inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations

inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations

Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG)

Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation?

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