Down syndrome-like acute megakaryoblastic leukemia in a patient with Cornelia de Lange syndrome

Vial, Yoann; Lachenaud, Julie; Verloès, Alain; Besnard, Marianne; Fenneteau, Odile; Lainey, Élodie; Marceau-Renaut, Alice; Preudhomme, Claude; Baruchel, André; Cavé, Hélène; Drunat, Séverine

doi:10.3324/haematol.2017.178590

Cited by 8 publications

(6 citation statements)

References 18 publications

(13 reference statements)

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“…Rare cases of leukemia have been reported in patients with CdLS, but were probably caused by other inherent aspects of this latter pathology. 38–40 The mutations in cohesin genes responsible for CdLS and leukemia insurgence are considered different for their pathophysiological output: cohesin mutations in tumors occur in somatic adult cells while germline cohesin mutations in CdLS patients occur in embryonic tissue. Moreover, cohesin mutations in cancer might not trigger, but contribute to tumorigenesis only with other mutations such as TET2 , 41 NPM1 , 9,42 DNMT3A 43 or FLT3 -ITD.…”

Section: Discussionmentioning

confidence: 99%

NIPBL: a new player in myeloid cell differentiation

et al. 2019

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The nucleophosmin 1 gene ( NPM1 ) is the most frequently mutated gene in acute myeloid leukemia. Notably, NPM1 mutations are always accompanied by additional mutations such as those in cohesin genes RAD21 , SMC1A , SMC3 , and STAG2 but not in the cohesin regulator, nipped B-like ( NIPBL ). In this work, we analyzed a cohort of adult patients with acute myeloid leukemia and NPM1 mutation and observed a specific reduction in the expression of NIPBL but not in other cohesin genes. In our zebrafish model, overexpression of the mutated form of NPM1 also induced downregulation of nipblb , the zebrafish ortholog of human NIPBL . To investigate the hematopoietic phenotype and the interaction between mutated NPM1 and nipblb , we generated a zebrafish model with nipblb downregulation which showed an increased number of myeloid progenitors. This phenotype was due to hyper-activation of the canonical Wnt pathway: myeloid cells blocked in an undifferentiated state could be rescued when the Wnt pathway was inhibited by dkk1b mRNA injection or indomethacin administration. Our results reveal, for the first time, a role for NIPBL during zebrafish hematopoiesis and suggest that an interplay between NIPBL/NPM1 may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive leukemic transformation.

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Section: Discussionmentioning

confidence: 99%

NIPBL: a new player in myeloid cell differentiation

et al. 2019

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“…alterations in genes encoding GATA1, cohesin complex components and signaling effectors together with acquired trisomy 21), with excellent outcome also seen for this subgroup of non-DS children [ 121 ]. DS–AMKL- like development has been reported in a patient with Cornelia de Lange syndrome, characterized by a mutation in NIPBL (encoding a cohesin complex component), with acquired trisomy 21, a GATA1 mutation, along with EZH2 and JAK/RAS alterations [ 122 ]. Moreover, underlying the impact of +21 in TMD development, rare TMD- like cases (occurrence of TMD in children without DS) have been described [ 123 – 125 ].…”

Section: Gain Of Chromosome 21 In Non-ds Leukemiamentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

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“…A germline-truncating SMC3 mutation in P6 was compatible with the clinical phenotype of CDL syndrome, a genome instability disorder called cohesinopathy ( SMC3 mutations account for 1% to 2% of patients with CDL syndrome). 19 Two patients with CDL-associated acute lymphoblastic leukemia (ALL) and AML have been previously reported, 20,21 but the CDL-MDS association presented here is new. CHEK2 mutations are implicated in familial breast cancer 22 and MDS.…”

Section: Resultsmentioning

confidence: 81%

“…The study cohort comprised five male patients and two female patients in whom myeloid malignancy was diagnosed at a median age of 17 (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) years after therapy for primary solid or hematologic tumors (P1-P5), arising from MDS related to Cornelia de Lange syndrome (CDL) (P6), or presenting with AML with MDS-related changes, multiple organ failure and multisystemic hyperinflammation (P7) (Table 1). The time from diagnosis of primary malignancy to development of sAML in P1-P5 ranged from 2.8 years to 15 years (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies

Hu¹,

Caldwell²,

Onciu³

et al. 2022

Blood Advances

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Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been no innovation in cytoreductive regimens. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML. We report the outcomes of seven young patients (six with newly diagnosed sMDS/AML and one with primary MDS/AML) uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange); and one MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. Patients received 1-3 cycles of CPX-351 (cytarabine 100mg/m2 plus daunorubicin 44mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.5-3.3 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML warranting prospective studies.

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Down syndrome-like acute megakaryoblastic leukemia in a patient with Cornelia de Lange syndrome

Cited by 8 publications

References 18 publications

NIPBL: a new player in myeloid cell differentiation

NIPBL: a new player in myeloid cell differentiation

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies

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