Impact of <i>KRAS</i> and <i>NRAS</i> mutations on outcomes in acute myeloid leukemia

Ali, Muhamad; Williams, Matthew; Corley, Elizabeth M.; Alkaabba, Fahad; Niyongere, Sandrine

doi:10.1080/10428194.2023.2190432

Cited by 5 publications

(1 citation statement)

References 13 publications

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“…Indeed, RAS mutations have been associated with higher relapse risk post-HMA treatment, such as AZA, or the Ven-AZA combination [ 54 , 65 – 68 ]. KRAS but not NRAS mutations were also found to be associated with inferior survival in AML, particularly in the context of HMA-based therapies (Table 2 ) [ 69 ]. Furthermore, a recent study validated a new molecular prognostic risk signature, called mPRS, tailored for AML patients treated with HMA and Ven.…”

Section: Prognostic Implicationsmentioning

confidence: 99%

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Alawieh,

Cysique-Foinlan,

Willekens

et al. 2024

Blood Cancer J.

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NRAS and KRAS activating point mutations are present in 10–30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.

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Section: Prognostic Implicationsmentioning

confidence: 99%

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Alawieh,

Cysique-Foinlan,

Willekens

et al. 2024

Blood Cancer J.

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Novel Mutations in Acute Erythroid Leukemia–A Case Report with Review of Literature

Jena,

Balasubramanian,

Hajra

et al. 2024

Indian J Hematol Blood Transfus

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Pathophysiology of Acute Myeloid Leukemia

Wachter,

Pikman

2024

Acta Haematol

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Acute myeloid leukemia (AML) is a biologically heterogenous disease arising in clonally proliferating hematopoietic stem cells. Sequential acquisition of mutations leads to expanded proliferation of clonal myeloid progenitors and failure of differentiation, leading to fulminant AML. Here we review the pathophysiology of AML with a focus on factors predisposing to AML development, including prior chemo- and radiation therapy, environmental factors, and germline predisposition. Increasing genomic characterization of AML and insight into mechanisms of its development will be critical to improvement in AML prognostication and therapy.

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Impact of KRAS and NRAS mutations on outcomes in acute myeloid leukemia

Cited by 5 publications

References 13 publications

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Novel Mutations in Acute Erythroid Leukemia–A Case Report with Review of Literature

Pathophysiology of Acute Myeloid Leukemia

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