No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.
Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3− CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.
Background Von Willebrand disease was diagnosed in two Afro‐Caribbean patients and sequencing of the VWF gene ( VWF ) revealed the presence of multiple variants located throughout the gene, including variants located in the D4 domain of VWF: p.(Pro2145Thrfs*5) in one patient and p.(Cys2216Phefs*9) in the other patient. Interestingly, D4 variants have not been studied often. Objectives Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods Recombinant VWF (rVWF), mutant or wild‐type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild‐type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results Homozygous expression of the p.(Cys2216Phefs*9)‐rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild‐type‐rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)‐rVWF exhibited reduced binding to type III collagen and αIIbβ3 integrin compared to wild‐type‐rVWF. Conclusions We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.
In 2015, a germline copy number variation of chromosome 14 (CNVdup14) including ATG2B and GSKIP genes was described as a predisposition genetic factor responsible of familial myeloproliferative neoplasms from French West Indies (Saliba et al, Nat Gen 2015), frequently progressing to AML. In this study, we looked at the presence of this CNVdup14 in a cohort of Caribbean islands patients (pts) with non-secondary aggressive hematological malignancies (HM). We also studied the expression of ATG2B and GSKIP genes in a cohort of acquired AML pts. This is a retrospective multicenter study of adults Caribbean islands pts treated at Gustave Roussy Cancer Center (Villejuif, France) and at the French West Indian hospitals (Martinique and Guadeloupe) between May 2000 and May 2018. We included pts with AML, acute undifferentiated leukemia (AUL), acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Pts with personal history of myeloproliferative or myelodysplastic syndromes before the onset of aggressive HM were not included in this study. The presence of the CNVdup14 was carried out by PCR analyses in all the pts. For the second part of the study, expression of ATG2B and GSKIP genes were assessed in newly diagnosed de novo AML pts with normal karyotype or trisomy 8 (samples from the GOELAMSTHEQUE) by quantitative RT-PCR and expressed as relative expression PPIA/HPRT/H2A.Z. One hundred pts were analyzed. Median age was 52 years (IQ 40-62) with male predominance (61%). Fifty eight pts came from Martinique, 42 pts from the rest of the Caribbean islands (including 28, 4, 3, 2 pts from Guadeloupe, Haiti, Saint Martin, Dominican Republic, respectively). Seventy eight pts had AML. Among them, according to revised MRC cytogenetic classification, 11 (14%) were favorable, 47 (60%) intermediate and 20 (26%) adverse. Seventeen pts had ALL, 3 LL, and 2 AUL. On the entire cohort, all except nine pts were treated with intensive chemotherapy, 80 reached complete remission, 29 relapsed, 46 pts died. Thirty two pts received hematopoietic stem cell transplantation (HSCT). Six pts were positive for the CNVdup14 by PCR (confirmed by SNP array in the 5 pts with leftover DNA available). All had an AML (no pts with favorable AML) and were originated from Martinique. These pts represented 14% of the 43 AML from Martinique in our cohort (17% if we excluded favorable AML). One was known to be part of an ATG2B/GSKIP family, 2 pts had no familial history of myeloid malignancies and 2 new families were discovered. Median white blood cell, hemoglobin and platelets counts were 17.7 G/l (IQ 6.7-48), 8.15 g/dl (6.9-9.7) and 58 G/l (20-132), respectively. Median age at AML diagnosis was 49 years (34-55), 3/6 (50%) had extramedullary localization compared to 11/78 (14%) for others AML pts. Karyotype was normal for 4, or showed a monosomy 7 for 2 pts. NGS panel showed distinct abnormalities compared to the entire cohort (Fig A). None had JAK2, MPL, CALR, P53, RUNX1, DNMT3A, FLT3-ITD mutations. All harbored an epigenetic and/or spliceosome mutation (IDH n=3, TET2 n=3, ASLX1 n=3, SRSF2 n=3). Five out of the six pts received intensive treatment and 4 achieved complete remission. Two received HSCT, 2 relapsed and 4 died. Median overall survival (OS) of the entire cohort was 35.7 months (22.5-89.5) and progression free survival (PFS) 27.6 months (15.6 -56.1). As CNVdup14 pts had AML only, we next evaluated survival according to the predisposition status in the AML cohort. Pts with CNVdup14 had a median OS and PFS of 19 (6.5-29) and 11.4 (6.5-29) months, respectively, compared with 52.6 (22.9-100.2) and 30 months (15.6-60) in CNV wild-type counterparts (PFS Fig B). We next evaluated ATG2B and GSKIP expression in a cohort of 46 random de novo AML pts (GOELAMS-LAM-IR-2006 multicenter trial). Median expression of ATG2B and GSKIP were 4.8 (2.6-12.9) and 5.3 (0.3-5.1) respectively. No CNVdup14 was detected. Interestingly we found a correlation between the two genes expression (Pearson Correlation Coefficients 0.55 and linear regression p< 0.001, Fig C). Expression of ATG2B and GSKIP was also correlated with leukocytosis (p=0.003 and p=0.07) (Fig D). We found no impact on OS and PFS. For the first time, we described a high percentage of the germline CNVdup14 in de novo AML pts from Martinique (14%). Moreover evaluation of ATG2B and GSKIP expression suggested that the role of theses 2 genes in leukemogenesis is not limited to pts with the CNVdup14. Figure. Figure. Disclosures de Botton: Agios: Research Funding; Celgene: Honoraria, Research Funding. Benabelali:CERBA laboratory: Employment.
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