Challenges in the use of NG2 antigen as a marker to predict MLL rearrangements in multi-center studies

Emerenciano, Mariana; Renaud, Gabriel; Santana, Mariana Oliveira; Barbieri, Caroline; Passetti, Fábio; Pombo‐de‐Oliveira, Maria S.

doi:10.1016/j.leukres.2011.03.006

Cited by 19 publications

(21 citation statements)

References 20 publications

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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: 99%

“…Despite the paucity of mutations observed in WGSeq studies, activating mutations in the RAS signaling pathway were found in half of the patients (9)(10)(11)(12), and previous screenings of infants with MA4 þ pro-B-ALL also found RAS mutations in approximately 25% of patients that correlated with poor outcome. KRAS mutations have also been associated with higher WBC counts (13) and found subclonally present at birth in neonatal blood spots (14). Furthermore, in a MA4 þ transgenic mouse model, activated KRAS accelerated leukemogenesis, although the latency/phenotype did not reproduce that seen in patients (15).…”

Section: Introductionmentioning

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: 99%

Section: Introductionmentioning

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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“…27 Although it might be associated with the high propensity of this leukemia to infiltrate the CNS, its exact contribution to disease evolution remains a mystery. [28][29][30] In infant B-ALL, MLL-r is associated with poorer outcome. In the Children's Cancer Group protocol CCG-1953, the 5-year event-free survival (EFS) for MLL-r infants was 34% compared with 60% with germline MLL.…”

Section: Clinical Features Of T(4;11)mentioning

confidence: 99%

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Sanjuán-Pla

Bueno

Prieto

et al. 2015

Blood

105

138

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Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a “multiple-and-sequential-hit” model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one “big-hit” might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models.

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“…KMT2A rearrangements are frequently accompanied by neuron‐glial antigen 2 (NG2) surface expression with the highest correlation accuracy in infant BCP‐ALL and lower accuracy in AML . Our patients showed NG2 expression in 13 of 28 cases (46%) with no preference to the particular KMT2A breakpoint localization.…”

Section: Discussionmentioning

confidence: 72%

Acute myeloid leukemia with t(10;11)(p11‐12;q23.3): Results of Russian Pediatric AML registration study

Zerkalenkova

Lebedeva

Казакова

et al. 2019

Int J Lab Hematology

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Introduction Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A‐MLLT10 is one of the common chimeric genes diagnosed in acute leukemia with KMT2A rearrangement (8%), especially in acute myeloid leukemia (AML; 18%). MLLT10 is localized in very close proximity to two other KMT2A partner genes at 10p11‐12—NEBL and ABI1, so they could not be distinguished by conventional cytogenetics. Methods In this work, we present a cohort of 28 patients enrolled into Russian Pediatric AML registration study carrying rearrangements between chromosomal regions 11q23.3 and 10p11‐12. G‐banding, FISH, reverse transcription PCR, and long‐distance inverse PCR were used to characterize the KMT2A gene rearrangements in these patients. Results We demonstrate that 25 patients harbor the KMT2A‐MLLT10 rearrangement, while three patients show the rare KMT2A rearrangements (2× KMT2A‐NEBL; 1× KMT2A‐ABI1). Conclusions Therefore, the combination of cytogenetic and molecular genetic methods is of high importance in diagnosing cases with t(10;11)(p11‐12;q23.3).

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Challenges in the use of NG2 antigen as a marker to predict MLL rearrangements in multi-center studies

Cited by 19 publications

References 20 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

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

Acute myeloid leukemia with t(10;11)(p11‐12;q23.3): Results of Russian Pediatric AML registration study

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