FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress

Libura, Marta; Asnafi, Vahid; Tu, Angela; Delabesse, Éric; Tigaud, Isabelle; Cymbalista, Florence; Bennaceur-Griscelli, Annelise; Villarèse, Patrick; Solbu, G.; Hagemeijer, Anne; Beldjord, Kheïra; Hermine, Olivier; Macintyre, Elizabeth

doi:10.1182/blood-2003-01-0162

Cited by 85 publications

(54 citation statements)

References 44 publications

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“…31,32 Similarly, MLL fusion proteins confer a remarkable growth/survival advantage. 31,33 Although none of our patients presented simultaneously both anomalies, a positive correlation has been previously reported between MLL intragenic abnormalities and FLT3 mutations. 33 FLT3 might be a therapeutic target in MLL-rearranged leukemias, in which mutations have been described in the activation loop of FLT3 resulting in constitutive activation.…”

Section: Discussionsupporting

confidence: 66%

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Thomas

Raffoux

Renneville

et al. 2010

Cancer

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BACKGROUND:Priming with granulocytic hematopoietic growth factors may modulate cell cycle kinetics of leukemic cells and render them more susceptible to phase‐specific chemotherapeutic agents. In a first report, we have shown that priming with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) may enhance complete remission (CR) rate and event‐free survival (EFS) in younger adults with acute myeloid leukemia (AML).METHODS:In this randomized trial, 259 patients with AML were randomized at baseline to receive or not receive GM‐CSF concurrently with all cycles of chemotherapy. The effects of GM‐CSF on survival were reported herein with a long‐term follow‐up and studied according to distinct biological subgroups defined on cytogenetics and molecular markers.RESULTS:The EFS rate was better in the GM‐CSF group (43% vs 34%; P = .04). GM‐CSF did not improve the outcome in patients from good risk subgroups, while patients from poor risk subgroups benefited from GM‐CSF therapy. In this population, the difference in terms of EFS probability was mainly observed in patients with high initial white blood cell count and in those with FLT3‐ITD or MLL rearrangement. When combining these 2 molecular abnormalities for comparison of the effect of GM‐CSF priming, the difference in terms of EFS was highly significant (5‐year EFS, 39% with GM‐CSF vs 8% without GM‐CSF; P = .007).CONCLUSIONS:Sensitization of leukemic cells and their progenitors by GM‐CSF appears as a plausible strategy for improving the outcome of patients with newly diagnosed AML. Patients with poor‐prognosis FLT3‐ITD or MLL rearrangement might be a good target population to further investigate priming strategies. Cancer 2010. © 2010 American Cancer Society.

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Section: Discussionsupporting

confidence: 66%

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Thomas

Raffoux

Renneville

et al. 2010

Cancer

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“…5,7,9,10,30 A positive correlation between MLL (mixed lineage leukemia) intragenic abnormalities (MLL partial tandem duplication (MLL-PTD) or DNA double-strand breakage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors) and FLT3 mutations (ITD and TKD) has been reported. 31 In contrast, there is an almost mutually exclusive occurrence of FLT3 and RAS mutations in AML samples. 32,33 Many studies have shown that FLT3-ITD has a negative impact on outcome in both adult and pediatric AML patients.…”

Section: Flt3mentioning

confidence: 98%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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“…This is in contrast to the frequency of MLL-PTD, which is equally low in pediatric AML, ranging from 1 to 10% depending on the screening method, 13,[37][38][39] as well as in adult AML, in the range of 5-10%. 37,[40][41][42][43][44][45][46][47] The different translocation partners of the rearranged MLL gene So far, more than 60 different fusion partners of MLL have been identified. Approximately 50% of pediatric AML cases with an MLL rearrangement consist of t(9;11)(p22;q23).…”

Section: Epidemiology Of Mll Aberrations In Pediatric Amlmentioning

confidence: 99%

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

et al. 2011

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Translocations involving the mixed-lineage leukemia (MLL) gene, localized at 11q23, comprise 15 to 20% of all pediatric acute myeloid leukemia (AML) cases. This review summarizes current knowledge about the etiology, biology, clinical characteristics and differences in outcome in MLL-rearranged pediatric AML. Furthermore, we discuss the role of cooperating events in MLL-rearranged pediatric AML, and future therapeutic strategies to improve outcome. We conclude that MLL-rearranged pediatric AML is a heterogeneous disease, and prognosis depends on various factors, for example, translocation partner, age, WBC and additional cytogenetic aberrations. The relationship of outcome with specific translocation partners requires that they be searched for in the diagnostic work-up of AML. To achieve further improvements in outcome, unraveling the biology of MLL-rearranged pediatric AML is warranted.

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FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress

Cited by 85 publications

References 44 publications

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

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