Distinct classes of c-Kit–activating mutations differ in their ability to promote RUNX1-ETO–associated acute myeloid leukemia

Nick, Heidi J.; Kim, Hyung‐Gyoon; Chang, Chia‐Wei; Harris, Kevin W.; Reddy, Vishnu; Klug, Christopher A.

doi:10.1182/blood-2011-02-338228

Cited by 36 publications

(29 citation statements)

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“…In addition, CBL-mediated processes of receptor ubiquitination and/or endocytosis in CBF-AML need to be clarified in future studies. Although it has been shown that KIT and MPL, which play important roles in AML1-ETO leukemia 52, 61–65 , are targets of CBL-mediated ubiquitination and degradation 21, 23 , we did not observe consistent upregulation of these receptor tyrosine kinases (RTKs) in AML1-ETO cells with CBL depletion/mutation (data not shown). Thus, downregulation of these receptors may not be the major mechanisms of CBL-meditated signal transduction.…”

Section: Discussioncontrasting

confidence: 63%

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

et al. 2015

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The t(8;21) rearrangement, which creates the AML1-ETO fusion protein, represents the most common chromosomal translocation in acute myeloid leukemia (AML). Clinical data suggest that CBL mutations are a frequent event in t(8;21) AML, but the role of CBL in AML1-ETO-induced leukemia has not been investigated. In this study, we demonstrate that CBL mutations collaborate with AML1-ETO to expand human CD34+ cells both in vitro and in a xenograft model. CBL depletion by shRNA also promotes the growth of AML1-ETO cells, demonstrating the inhibitory function of endogenous CBL in t(8;21) AML. Mechanistically, loss of CBL function confers hyper-responsiveness to thrombopoietin and enhances STAT5/AKT/ERK/Src signaling in AML1-ETO cells. Interestingly, we found the protein tyrosine phosphatase UBASH3B/Sts-1, which is known to inhibit CBL function, is upregulated by AML1-ETO through transcriptional and miR-9-mediated regulation. UBASH3B/Sts-1 depletion induces an aberrant pattern of CBL phosphorylation and impairs proliferation in AML1-ETO cells. The growth-inhibition caused by UBASH3B/Sts-1 depletion can be rescued by ectopic expression of CBL mutants, suggesting that UBASH3B/Sts-1 supports the growth of AML1-ETO cells partly through modulation of CBL function. Our study reveals a role of CBL in restricting myeloid proliferation of human AML1-ETO-induced leukemia, and identifies UBASH3B/Sts-1 as a potential target for pharmaceutical intervention.

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Section: Discussioncontrasting

confidence: 63%

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

et al. 2015

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“…[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. 52 Retrospective studies have assessed the impact of KIT mutations as a prognostic marker in t(8;21) and inv(16) AML (Table 1).…”

Section: Kitmentioning

confidence: 99%

“…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. 52 Retrospective studies have assessed the impact of KIT mutations as a prognostic marker in t(8;21) and inv(16) AML (Table 1). Although in several but not all studies in t(8;21) AML, KIT mutations, in particular those affecting the A-loop, have been associated with unfavorable outcome, the prognostic impact of KIT mutations in inv(16) AML is less clear ( Table 1).…”

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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“…Similarly, high transcript levels of AE9a also correlated with t(8;21) disease relapse (16,43 signals from cooperating events play a role in how AE or AE9a affect downstream signals. A number of cooperating oncogenes have been shown to promote leukemic transformation with full-length AE (6,(8)(9)(10)(11)(12)(13). A recent study demonstrated that various c-Kit-activating mutations cooperate with AEtr (the truncated form of AE, similar to AE9a) to initiate an oncogenic-like phenotype in human mobilized PB CD34 + cells (44).…”

Section: Discussionmentioning

confidence: 99%

“…Conditional expression and transduction-transplantation approaches have demonstrated that expression of AE provides self-renewal signaling to hematopoietic stem/progenitor cells (HSPCs) but does not induce transformation in the absence of additional cooperating events (3-7). Several such cooperating events have been identified, including overexpression of WT1, mutant c-KIT, TEL-PDGFRB, FLT3-ITD, loss of p21, and treatment with the DNA-damaging agent ENU (6,(8)(9)(10)(11)(12)(13). Conversely, C-terminal truncation of AE through frameshift mutation (AML1-ETOtr) or alternative splicing at exon 9 (AE9a) leads to acute myeloid leukemia (AML) transformation of murine HSPCs (14, 15).…”

mentioning

confidence: 99%

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

Link

Lin

Shrestha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Chromosomal translocation 8;21 is found in 40% of the FAB M2 subtype of acute myeloid leukemia (AML). The resultant in-frame fusion protein AML1-ETO (AE) acts as an initiating oncogene for leukemia development. AE immortalizes human CD34 + cord blood cells in longterm culture. We assessed the transforming properties of the alternatively spliced AE isoform AE9a (or alternative splicing at exon 9), which is fully transforming in a murine retroviral model, in human cord blood cells. Full activity was realized only upon increased fusion protein expression. This effect was recapitulated in the AE9a murine AML model. Cotransduction of AE and AE9a resulted in a strong selective pressure for AE-expressing cells. In the context of AE, AE9a did not show selection for increased expression, affirming observations of human t(8;21) patient samples where full-length AE is the dominant protein detected. Mechanistically, AE9a showed defective transcriptional regulation of AE target genes that was partially corrected at high expression. Together, these results bring an additional perspective to our understanding of AE function and highlight the contribution of oncogene expression level in t(8;21) experimental models.T he t(8;21)(q22;q22) chromosomal translocation comprises the N-terminal DNA binding domain of AML1 (RUNX1) and nearly the entire ETO (RUNX1T1) gene, forming the fusion protein AML1-ETO (AE) (1, 2). Conditional expression and transduction-transplantation approaches have demonstrated that expression of AE provides self-renewal signaling to hematopoietic stem/progenitor cells (HSPCs) but does not induce transformation in the absence of additional cooperating events (3-7). Several such cooperating events have been identified, including overexpression of WT1, mutant c-KIT, TEL-PDGFRB, FLT3-ITD, loss of p21, and treatment with the DNA-damaging agent ENU (6,(8)(9)(10)(11)(12)(13). Conversely, C-terminal truncation of AE through frameshift mutation (AML1-ETOtr) or alternative splicing at exon 9 (AE9a) leads to acute myeloid leukemia (AML) transformation of murine HSPCs (14, 15). The AE9a transcript is expressed in ∼70% of t(8;21) + AML patients, along with full-length AE (14, 16). AE9a lacks the conserved ETO domains NHR3/4, whose interaction with corepressor proteins such as N-CoR/SMRT and HDACs is important for transcriptional repression (17)(18)(19)(20). Despite maintaining some corepressor interaction, AE9a has greatly diminished N-CoR and SMRT interaction and is a much less potent transcriptional repressor than full-length AE (17,(19)(20)(21)(22). The AML1-ETOtr mutant showed altered regulation of cell cycle proteins, thereby providing a proliferative advantage in K562 cells relative to AE (15). Recently, DeKelver et al. showed that the interaction between N-CoR and the NHR4 domain plays an inhibitory role in leukemia development in the context of full-length AE (23). However, analysis of a small cohort of t(8;21) patient samples did not detect any mutations in the NHR4 domain, indicating that such mutations are probabl...

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Distinct classes of c-Kit–activating mutations differ in their ability to promote RUNX1-ETO–associated acute myeloid leukemia

Cited by 36 publications

References 50 publications

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1-ETO

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

Supraphysiologic levels of the AML1-ETO isoform AE9a are essential for transformation

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