Functional Properties of <i>KIT</i> Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia

Tarlock, Katherine; Alonzo, Todd A.; Wang, Yi Cheng; Gerbing, Robert B.; Ries, Rhonda E.; Loken, Michael R.; Pardo, Laura; Hylkema, Tiffany; Joaquin, Jason; Sarukkai, Leela; Raimondi, Susana C.; Hirsch, Betsy A.; Sung, Lillian; Aplenc, Richard; Bernstein, Irwin D.; Gamis, Alan S.; Meshinchi, Soheil; Pollard, Jessica A.

doi:10.1158/1078-0432.ccr-18-1897

Cited by 44 publications

(60 citation statements)

References 65 publications

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“…KIT mutations have been found in approximately 30% of CBF-AML patients who have chromosome aberrations [31–33]. Recent studies showed that active KIT mutations are correlated with a poor prognosis in AML patients [31, 32].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies showed that active KIT mutations are correlated with a poor prognosis in AML patients [31, 32]. The major activating KIT mutations are found at D816 and N822 (26 cases and 14 cases in 63 KIT mutation-positive patients, respectively) [33]. Although spatio-temporal analyses of KIT D816V signals have been performed [24, 25, 28], it is unclear whether the N822K mutation in leukemia affects KIT localization and the signal platform.…”

Section: Introductionmentioning

confidence: 99%

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N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

Obata¹,

Hara²,

Shiina³

et al. 2019

Cell Commun Signal

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Background KIT tyrosine kinase is expressed in mast cells, interstitial cells of Cajal, and hematopoietic cells. Permanently active KIT mutations lead these host cells to tumorigenesis, and to such diseases as mast cell leukemia (MCL), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML). Recently, we reported that in MCL, KIT with mutations ( D816V , human; D814Y , mouse) traffics to endolysosomes (EL), where it can then initiate oncogenic signaling. On the other hand, KIT mutants including KIT D814Y in GIST accumulate on the Golgi, and from there, activate downstream. KIT mutations, such as N822K , have been found in 30% of core binding factor-AML (CBF-AML) patients. However, how the mutants are tyrosine-phosphorylated and where they activate downstream molecules remain unknown. Moreover, it is unclear whether a KIT mutant other than KIT D816V in MCL is able to signal on EL. Methods We used leukemia cell lines, such as Kasumi-1 ( KIT N822K , AML), SKNO-1 ( KIT N822K , AML), and HMC-1.1 ( KIT V560G , MCL), to explore how KIT transduces signals in these cells and to examine the signal platform for the mutants using immunofluorescence microscopy and inhibition of intracellular trafficking. Results In AML cell lines, KIT N822K aberrantly localizes to EL. After biosynthesis, KIT traffics to the cell surface via the Golgi and immediately migrates to EL through endocytosis in a manner dependent on its kinase activity. However, results of phosphorylation imaging show that KIT is preferentially activated on the Golgi. Indeed, blockade of KIT N822K migration to the Golgi with BFA/M-COPA inhibits the activation of KIT downstream molecules, such as AKT, ERK, and STAT5, indicating that KIT signaling occurs on the Golgi. Moreover, lipid rafts in the Golgi play a role in KIT signaling. Interestingly, KIT V560G in HMC-1.1 migrates and activates downstream in a similar manner to KIT N822K in Kasumi-1. Conclusions In AML, KIT N822K mislocalizes to EL. Our findings, however, suggest that the mutant transduces phosphorylation signals on lipid rafts of the Golgi in leukemia cells. Unexpectedly, the KIT V560G signal platform in MCL is similar to that of KIT N822K in AML. These observations provide new insights into the pathogenic role of KIT mutants as well as that of other mutant molecules. Electronic supplementary material The online version of this article (10.1186/s12964-01...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

Obata¹,

Hara²,

Shiina³

et al. 2019

Cell Commun Signal

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“…Of the KITmuts, the codon change D816 was more associated with the significant difference in response than was N822 in t(8; 21) AML, a finding that is supported by in vitro studies demonstrating a positive association of the D816 mutation with stronger KIT phosphorylation and subsequent signalling activation 26,27 . In clinical practice, sequencing results are often not available fast enough, making the development of approaches that can quickly screen for the existence of KIT-D816 necessary.…”

Section: Discussionmentioning

confidence: 74%

“…iii) Post-remission high-dose Ara-C might still exert its role on residual KITmut clones. iv) Mutations in KIT have also been reported to be frequently lost at disease relapse 27,40 .…”

Section: (Ii)mentioning

confidence: 99%

Clinical heterogeneity under induction with different dosages of cytarabine in core binding factor acute myeloid leukaemia

Wang

Zhang

Hua

et al. 2020

Sci Rep

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Repeated cycles of post-remission high-dose cytarabine (Ara-C) have been suggested to improve survival in core binding factor (CBF) acute myeloid leukaemia (AML). High-dose Ara-C used for induction regimens has also been reported to be associated with increased treatment-related mortality (TRM). Few data are available about intermediate-dose Ara-C serving as induction therapy. The aim of our study was to compare the tolerance and outcomes of standard-and intermediate-dose levels of Ara-C as induction in CBF AML and to analyse the clinical heterogeneity of the two AML entities under these induction settings. We retrospectively investigated the outcomes in adults with CBF AML induced with regimens based on standard-dose Ara-C at 100 to 200 mg/m 2 or intermediate-dose Ara-C at 1,000 mg/ m 2 . In total, 152 patients with t(8; 21) and 54 patients with inv(16) AML were administered an induction regimen containing anthracyclines plus either standard-or intermediate-dose Ara-C. After a single course of induction, the complete remission (CR) rate in the inv(16) cohort was 52/52 (100%), higher than the 127/147 (86.4%) in the t(8; 21) cohort (P = 0.005). Intermediate-dose Ara-C (HR = 9.931 [2.135-46.188], P = 0.003) and negative KITmut (HR = 0.304 [0.106-0.874], P = 0.027) independently produced an increased CR rate in the t(8; 21) cohort. Positive CD19 expression (HR = 0.133 [0.045-0.387], P = 0.000) and sex (male) (HR = 0.238 [0.085-0.667], P = 0.006) were associated with superior leukaemia-free survival (LFS) in the t(8; 21) cohort independently of KITmut status or the induction regimen. We conclude that intermediate-dose Ara-C is superior to standard-dose Ara-C for induction of remission in t(8; 21) AML, and CD19 status and sex independently confer prognostic significance for LFS. The KITmut status alone does not have an independent effect on survival in t(8; 21) AML. More intensive induction therapy is unnecessary in inv(16) AML.Acute myeloid leukaemia (AML) with t(8; 21)(q22; q22) and AML with inv(16)(p13.1q22)/t(16; 16)(p13.1; q22) are together referred to as core binding factor (CBF) AML 1-4 , which constitutes approximately 5-8% of all de novo AML cases 5-7 . Both have been recognized as distinct diseases by the World Health Organization classification of myeloid neoplasms and acute leukaemia 8 .Overall, CBF AML has a relatively favourable clinical outcome compared to other cytogenetic subtypes. Repeated cycles of high-dose cytarabine (Ara-C) for intensification during post-remission treatment can improve survival outcomes 9-12 . However, there is considerable clinicopathological heterogeneity within this AML subset, as demonstrated by the relapse incidence reaching up to 40% and the overall survival (OS) rate of 40-60% 13-17 .Ara-C at a daily dose of 100 to 200 mg/m 2 for 7 days as induction therapy is the most widely applied strategy in most centres. Several clinical trials evaluating high-dose Ara-C as induction therapy in AML have been conducted, with results differing and the majority reporting increased treat...

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“…KIT mutations are common in CBFL and have been associated with worse prognosis (shorter disease-free survival, relapse-free survival, event-free survival, overall survival) [147]. A phase III study of gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories) showed that GO abrogated the negative prognostic effect of exon 17 (E17) mutations in treated patients [148]. Moreover, the outcome of patients harboring KIT mutations in the Cancer and Leukemia Group B (CALGB) study, appeared not to be worse than that of patients with KIT wild-type after treatment with dasatinib, implying that a potentially adverse impact of KIT mutations might be abrogated in treated patients [144].…”

Section: Molecular Targeted Therapy Of Cbfl: the Progress And Future mentioning

confidence: 99%

Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

Beghini

2019

Cancers

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Acute myeloid leukemia (AML), the most common acute leukemia in adults, is a heterogeneous malignant clonal disorder arising from multipotent hematopoietic progenitor cells characterized by genetic and concerted epigenetic aberrations. Core binding factor-Leukemia (CBFL) is characterized by the recurrent reciprocal translocations t(8;21)(q22;q22) or inv(16)(p13;q22) that, expressing the distinctive RUNX1-RUNX1T1 (also known as Acute myeloid leukemia1-eight twenty-one, AML1-ETO or RUNX1/ETO) or CBFB-MYH11 (also known as CBFβ-SMMHC) translocation product respectively, disrupt the essential hematopoietic function of the CBF. In the past decade, remarkable progress has been achieved in understanding the structure, three-dimensional (3D) chromosomal topology, and disease-inducing genetic and epigenetic abnormalities of the fusion proteins that arise from disruption of the CBF subunit alpha and beta genes. Although CBFLs have a relatively good prognosis compared to other leukemia subtypes, 40–50% of patients still relapse, requiring intensive chemotherapy and allogenic hematopoietic cell transplantation (alloHCT). To provide a rationale for the CBFL-associated altered hematopoietic development, in this review, we summarize the current understanding on the various molecular mechanisms, including dysregulation of Wnt/β-catenin signaling as an early event that triggers the translocations, playing a pivotal role in the pathophysiology of CBFL. Translation of these findings into the clinical setting is just beginning by improvement in risk stratification, MRD assessment, and development of targeted therapies.

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Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia

Cited by 44 publications

References 65 publications

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

N822K- or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells

Clinical heterogeneity under induction with different dosages of cytarabine in core binding factor acute myeloid leukaemia

Core Binding Factor Leukemia: Chromatin Remodeling Moves Towards Oncogenic Transcription

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