Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study

Kawashima, Naomi; Akashi, Akimi; Nagata, Yasunobu; Kihara, Rika; Ishikawa, Yuichi; Asou, Norio; Ohtake, Shigeki; Miyawaki, Shuichi; Sakura, Toru; Ozawa, Yukiyasu; Usui, Noriko; Kanamori, Heiwa; Imai, Kiyotoshi; Suehiro, Yutaka; Kïtamura, Kazuo; Sakaida, Emiko; Takeshita, Akira; Suzushima, Hitoshi; Naoe, Tomoki; Matsumura, Itaru; Miyazaki, Yasushi; Ogawa, Seishi; Kiyoi, Hitoshi

doi:10.1007/s00277-018-3492-5

Cited by 19 publications

(17 citation statements)

References 24 publications

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“…FLT3 ‐ITD is particularly associated with a variant morphology of APL and the presence of the short breakpoint cluster region 3 PML‐RARA isoforms . In addition, FLT3 mutations are infrequent in core‐binding factor AML (CBF‐AML) consisting of AML with RUNX1‐RUNX1T1 and CBFB‐MYH11 , although FLT3 ‐TKD is frequently found in AML with CBFB‐MYH11 . FLT3 mutations frequently overlap with NPM1 , DNMT3A and KMT2A partial tandem duplication ( KMT2A ‐PTD) mutations but are mutually exclusive with KIT , K/NRAS and CEBPA ‐double ( CEBPA ‐D) mutations (Figure B) .…”

Section: Clinical Significance Of Flt3 Mutationsmentioning

confidence: 80%

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

2019

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FMS‐like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3‐ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3‐TKD). Both mutant FLT3 molecules are activated through ligand‐independent dimerization and trans‐phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti–apoptosis. Because high‐dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.

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Section: Clinical Significance Of Flt3 Mutationsmentioning

confidence: 80%

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

2019

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“…1 However, several prognostic factors, including genetic alterations, have been demonstrated. [2][3][4][5][6][7][8] In particular, KIT mutation has been suggested to be associated with a poor prognosis in AML patients with RUNX1-RUNX1T1 or CBFB-MYH11. 3,5,[9][10][11][12] Many types of KIT mutations have been identified in cancer cells, but there are 3 mutation hot-spots (exon 8, exon 10-11, and exon 17) in AML.…”

Section: Introductionmentioning

confidence: 99%

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11

et al. 2020

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“…The most puzzling fact about ZBTB7A mutations in AML is their exclusive presence in the context of core binding factor leukemia, mainly in t(8;21) AML [1][2][3][4][5][6], which suggests a specific collaboration between RUNX1-RUNX1T1 and loss of ZBTB7A function. Of note, it was previously reported that RUNX1-RUNX1T1 causes a block of the monocytic and erythrocytic linages in favor of granulocytic differentiation in mouse and zebrafish [9,23].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we and others found the transcription factor ZBTB7A mutated in acute myeloid leukemia (AML) with translocation t (8;21), at frequencies ranging from 9.4 to 23% [1][2][3][4][5][6]. Hotspot mutations result either in loss (A175fs) or alteration (R402) of the C-terminal zinc finger domain, which is critical for DNA-binding of ZBTB7A [1].…”

Section: Introductionmentioning

confidence: 99%

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

et al. 2020

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ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1-RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-D-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

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Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study

Cited by 19 publications

References 24 publications

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

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