Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

Driessen, Emma M. C.; Roon, Eddy H.J. Van; Spijkers-Hagelstein, J A P; Schneider, Pauline; Lorenzo, Paola De; Valsecchi, Maria Grazia; Pieters, Rob; Stam, Ronald W.

doi:10.3324/haematol.2012.067983

Cited by 89 publications

(124 citation statements)

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“…KRAS mutations have also been associated with higher WBC counts and poor disease evolution (36) and have been found subclonally present at birth in matched neonatal blood spot diagnosis samples (14). Furthermore, in a MA4 þ transgenic mouse model, activated KRAS accelerated leukemogenesis, although the phenotype did not reproduce that seen in patients (15).…”

Section: Discussionmentioning

confidence: 94%

“…In sharp contrast with its dismal clinical evolution, independent recent WGSeq studies have revealed a silent mutational landscape in MLL-r infant B-ALL (9-12), supporting the possibility that MA4 functions as a single oncogenic driver that suffices to spawn aggressive B-ALL. Despite the paucity of mutations observed in WGSeq studies, activation of FLT-3 and/or RAS was subclonally found in 30% to 50% of patients (9)(10)(11)(12) and correlated with poor outcome (36,47). Using CB-CD34…”

Section: Discussionmentioning

confidence: 99%

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Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

et al. 2016

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The MLL-AF4 (MA4) fusion gene is the genetic hallmark of an aggressive infant pro-B-acute lymphoblastic leukemia (B-ALL). Our understanding of MA4-mediated transformation is very limited. Whole-genome sequencing studies revealed a silent mutational landscape, which contradicts the aggressive clinical outcome of this hematologic malignancy. Only RAS mutations were recurrently detected in patients and found to be associated with poorer outcome. The absence of MA4-driven B-ALL models further questions whether MA4 acts as a single oncogenic driver or requires cooperating mutations to manifest a malignant phenotype. We explored whether KRAS activation cooperates with MA4 to initiate leukemia in cord blood-derived CD34

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

et al. 2016

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“…[45][46][47][48] This uncontrolled RAS activation is mainly due to known somatic activating mutations, 49,50 or to the constitutive activation of several receptor tyrosine kinases, such as colony stimulating factor 1 and FLT3, or derives from the loss of function of tumor suppressor genes, such as NF1 and PTPN11. 51 Even though the RAS pathway is overactivated in MLL-AF6-positive pediatric patients in our cohort, we never found mutations in the RAS gene, confirming our hypothesis of an active role of the chimera MLL-AF6 as the driving force of the observed aberrant RAS pathway activation.…”

Section: 46mentioning

confidence: 99%

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confidence: 99%

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

Manara

Baron

Tregnago

et al. 2014

Blood

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Key Points• MLL-AF6 leads to aberrant activation of RAS and its downstream targets.• RAS targeting is a novel potential therapeutic strategy in AML patients carrying t(6;11).A rare location, t(6;11)(q27;q23) (MLL-AF6), is associated with poor outcome in childhood acute myeloid leukemia (AML). The described mechanism by which MLL-AF6, through constitutive self-association and in cooperation with DOT-1L, activates aberrant gene expression does not explain the biological differences existing between t(6;11)-rearranged and other MLL-positive patients nor their different clinical outcome. Here, we show that AF6 is expressed in the cytoplasm of healthy bone marrow cells and controls rat sarcoma viral oncogene (RAS)-guanosine triphosphate (GTP) levels. By contrast, in MLL-AF6-rearranged cells, AF6 is found localized in the nucleus, leading to aberrant activation of RAS and of its downstream targets. Silencing MLL-AF6, we restored AF6 localization in the cytoplasm, thus mediating significant reduction of RAS-GTP levels and of cell clonogenic potential. The rescue of RAS-GTP levels after MLL-AF6 and AF6 co-silencing confirmed that MLL-AF6 oncoprotein potentiates the activity of the RAS pathway through retention of AF6 within the nucleus. Exposure of MLL-AF6-rearranged AML blasts to tipifarnib, a RAS inhibitor, leads to cell autophagy and apoptosis, thus supporting RAS targeting as a novel potential therapeutic strategy in patients carrying t(6;11). Altogether, these data point to a novel role of the MLL-AF6 chimera and show that its gene partner, AF6, is crucial in AML development. (Blood. 2014;124(2):263-272) IntroductionThe mixed lineage leukemia (MLL) protein is a histone H3 lysine 4-specific methyltransferase, commonly associated with transcriptional activation.1 MLL is essential for both embryonic development and normal hematopoiesis, mainly through transcriptional regulation of the homeobox (HOX) gene.2 Chromosome translocations involving MLL locus are 1 of the major genetic lesions leading to acute leukemia. MLL translocations are detected in up to 80% of infant acute leukemia and in approximately 10% to 15% of childhood acute myeloid leukemia (AML).3,4 Aberrant proteins resulting from translocations, duplications, or amplifications of the MLL gene cause alteration of the differentiation program with severe effects on leukemogenesis. 5,6 To date, more than 60 fusion partners of MLL have been described, which result in AML, acute lymphoid, and biphenotypic or chemotherapy-related leukemias. 7,8 The underlying mechanisms for MLL-mediated leukemogenesis have been extensively studied; however, they still remain elusive for many of the described translocations. MLL-rearranged AML is, in fact, a heterogeneous disease, which depends on the MLL partner gene for its biological and clinical features, such as gene expression and genomic imbalances. 4 Among diverse fusion genes, the 1 that has been consistently associated with the worst outcome both in adult and pediatric AML is MLL-AF6. 9The t(6;11)(q27;q23) translocatio...

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“…5,6 Although RAS mutations have not been shown to affect prognosis in childhood ALL in general, 6 they are a poor prognostic sign in MLL-rearranged ALL. 7 Irving et al detect a RAS mutation frequency similar to that seen in diagnostic cases, but in contrast to RAS mutations at diagnosis, they found that mutations at first relapse were associated with dismal prognostic features, such as a higher proportion of early relapses and central nervous system (CNS) involvement. The role of RAS mutations in relapsed ALL is poorly understood, with a handful of reported cases showing mutations both appearing and disappearing at relapse compared with diagnosis.…”

mentioning

confidence: 99%

Risk of RAS in relapsed childhood ALL

Paulsson

2014

Blood

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Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

Cited by 89 publications

References 36 publications

Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

Risk of RAS in relapsed childhood ALL

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