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"Bill, Marius"
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Disciplined entrepreneurship workbook
\"A practical manual for implementing the framework, the 'Disciplined Entrepreneurship Workbook' breaks down the steps and takes you deeper, highlighting critical points that can make or break a fledgling business.\"--Back cover.
Book
Knockout of both miR-15/16 loci induces acute myeloid leukemia
MicroRNAs (miRNAs) have been extensively reported to be associated with hematological malignancies. The loss of miR-15a/16–1 at chromosome 13q14 is a hallmark of most of human chronic lymphocytic leukemia (CLL). Deletion of murine miR-15a/16–1 and miR-15b/16–2 has been demonstrated to promote B cell malignancies. Here, we evaluate the biological role of miR-15/16 clusters, crossbreeding miR-15a/16–1 and miR-15b/16–2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months with a penetrance of 70%. These mice showed a significant enlargement of spleen and abnormal swelling of lymph nodes. Flow cytometry characterization demonstrated an expanded CD11b/Gr-1 double-positive myeloid population both in spleen and in bone marrow. The transplantation of splenocytes harvested from double-KO mice into wild-type recipient mice resulted in the development of myeloproliferative disorders, as observed in the donors. In vivo, miR-15/16 cluster deletion up-regulated the expression of Cyclin D1, Cyclin D2, and Bcl-2. Taken together, our findings identify a driver oncogenic role for miR-15/16 cluster deletion in different leukocytic cell lineages.
Journal Article
Disruption of the C/EBPα—miR-182 balance impairs granulocytic differentiation
Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal
CEBPA
mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.
C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.
Journal Article
Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia
Epithelial growth factor-like 7 (EGFL7) is a protein that is secreted by endothelial cells and plays an important role in angiogenesis. Although EGFL7 is aberrantly overexpressed in solid tumors, its role in leukemia has not been evaluated. Here, we report that levels of both EGFL7 mRNA and EGFL7 protein are increased in blasts of patients with acute myeloid leukemia (AML) compared with normal bone marrow cells. High EGFL7 mRNA expression associates with lower complete remission rates, and shorter event-free and overall survival in older (age ≥60 y) and younger (age <60 y) patients with cytogenetically normal AML. We further show that AML blasts secrete EGFL7 protein and that higher levels of EGFL7 protein are found in the sera from AML patients than in sera from healthy controls. Treatment of patient AML blasts with recombinant EGFL7 in vitro leads to increases in leukemic blast cell growth and levels of phosphorylated AKT. EGFL7 blockade with an anti-EGFL7 antibody reduced the growth potential and viability of AML cells. Our findings demonstrate that increased EGFL7 expression and secretion is an autocrine mechanism supporting growth of leukemic blasts in patients with AML.
Journal Article
Precision oncology in AML: validation of the prognostic value of the knowledge bank approach and suggestions for improvement
Recently, a novel knowledge bank (KB) approach to predict outcomes of individual patients with acute myeloid leukemia (AML) was developed using unbiased machine learning. To validate its prognostic value, we analyzed 1612 adults with de novo AML treated on Cancer and Leukemia Group B front-line trials who had pretreatment clinical, cytogenetics, and mutation data on 81 leukemia/cancer-associated genes available. We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate the predictive values of the KB algorithm and other risk classifications. The KB algorithm predicted 3-year overall survival (OS) probability in the entire patient cohort (AUC
KB
= 0.799), and both younger (< 60 years) (AUC
KB
= 0.747) and older patients (AUC
KB
= 0.770). The KB algorithm predicted non-remission death (AUC
KB
= 0.860) well but was less accurate in predicting relapse death (AUC
KB
= 0.695) and death in first complete remission (AUC
KB
= 0.603). The KB algorithm’s 3-year OS predictive value was higher than that of the 2017 European LeukemiaNet (ELN) classification (AUC
2017ELN
= 0.707,
p
< 0.001) and 2010 ELN classification (AUC
2010ELN
= 0.721,
p
< 0.001) but did not differ significantly from that of the 17-gene stemness score (AUC
17-gene
= 0.732,
p
= 0.10). Analysis of additional cytogenetic and molecular markers not included in the KB algorithm revealed that taking into account atypical complex karyotype, infrequent recurrent balanced chromosome rearrangements and mutational status of the
SAMHD1
,
AXL
and
NOTCH1
genes may improve the KB algorithm. We conclude that the KB algorithm has a high predictive value that is higher than those of the 2017 and 2010 ELN classifications. Inclusion of additional genetic features might refine the KB algorithm.
Journal Article
Cell cycle regulator MYBL2 is a distinct vulnerability in acute myeloid leukemia
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of myeloid blasts in the bone marrow. Despite the availability of potential curative treatments, patients frequently experience unfavorable outcomes. One crucial aspect contributing to relapse is the plasticity of leukemic clones, which enables them to switch between active proliferation and dormancy. The adaptability of AML underscores the need for novel therapies targeting AML-specific proteins. To address this, genome-wide CRISPR screens can be utilized to identify cancer entity-specific vulnerabilities. Leveraging publicly available functional genomics datasets and comparing AML with non-AML cancer cell lines, we identified a significant dependency on the cell cycle-regulating gene
MYBL2
in AML. We describe MYBL2 as a key driver of AML cell growth and proliferation, highlighting its established role as a cell cycle regulator. Also, our findings uncover its previously unrecognized function as an inhibitor of cellular senescence. A knockdown of
MYBL2
induces cell cycle arrest in the G2/M phase with subsequent induction of apoptosis in vitro, and reduces leukemic burden in a patient-derived xenograft (PDX) model in vivo. Interestingly, some AML cells evade apoptosis and enter a senescent-like phenotype upon
MYBL2
-knockdown, which is reversible upon re-expression of
MYBL2
. Finally, analyses of clinical data from two publicly available patient cohorts demonstrate a lower probability of survival in patients with higher
MYBL2
expression, further hinting at the potential relevance of MYBL2 in AML. In conclusion, our findings demonstrate the essential role of MYBL2 in AML, governing the balance between cell proliferation, cell survival and senescence, ultimately influencing the fate of AML cells.
Journal Article
Quantifying NPM1 MRD in AML patients prior to allogeneic stem cell transplantation: Where to draw the line?
Adapting the 0.01% NPM1/ABL1 cut-off, we observed the clearest separation of the cumulative incidence of relapse (CIR, p < 0.001, after 2 years 4% vs. 66%, Figure , resulting in a 93.8% relative risk reduction for relapse after 2 years for MRD-negative [n = 50] compared to MRD-positive [n = 31] patients), as well as OS curves (p < 0.001, after 2 years 76% vs. 38%; Supporting Information S1: Figure ). Only at the highest cut-off of 10% NPM1/ABL1 copy numbers, all MRD-positive patients relapsed, but at this cut-off “MRD-negative” patients had a CIR as high as 25% after 2 years (Figure ), with a negative predictive value of only 0.72 (Supporting Information S1: Table ). [...]in our cohort the negative impact of a low or high NPM1 MRD at HSCT was not modified by the presence or absence of an FLT3-ITD (Supporting Information S1: Figure ), which might be a result of the restricted sample size. Remarkably, outcomes of MRD-positive patients after reduced-intensity HSCT improved when the conditioning regimen was melphalan-based, showing potential for clinical intervention. Since mutated NPM1 has been described as immunogenic, NPM1-mutated patients may benefit from HSCT consolidation. [...]OS did not differ (p > 0.99) as MRD-positive patients with a chronic GvHD tended to have higher nonrelapse mortality (NRM; p = 0.06). [...]patients transplanted with positive NPM1 MRD may benefit from immunologic interventions such as donor lymphocyte infusions to augment GvL but should be selected very carefully to avoid increasing NRM.
Journal Article
Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A
Balanced rearrangements involving the KMT2A gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/KMT2A rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/KMT2A rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/KMT2A rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/KMT2A rearrangements with material for molecular studies available. Patients with 11q23/KMT2A rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (KRAS, NRAS, and PTPN11) in 32% of patients. KRAS mutations occurred more often in patients with t(6;11)(q27;q23)/KMT2A-AFDN compared with patients with the other 11q23/KMT2A subsets. Specific gene mutations were too infrequent in patients with specific 11q23/KMT2A rearrangements to assess their associations with outcomes. We demonstrate that younger (age 60 y) patients with t(9;11)(p22;q23)/KMT2A-MLLT3 had better outcomes than patients with other 11q23/KMT2A rearrangements and those without 11q23/KMT2A rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/KMT2A rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.
Journal Article