Five New Pedigrees with Inherited RUNX1 Mutations Causing Familial Platelet Disorder with Propensity to Myeloid Malignancy (FPD/AML)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5067-5067
Author(s):  
Carolyn J Owen ◽  
Cynthia L Toze ◽  
Anna Koochin ◽  
Donna L. Forrest ◽  
Clayton A. Smith ◽  
...  
Keyword(s):  
Young Patients ◽  
Trisomy 13 ◽  
Degree Relative ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Myeloid Malignancy ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Inherited Mutations ◽  
Runx1 Mutation

Abstract Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterised by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first- degree relative with MDS/AML and detected inherited mutations in RUNX1 in 5 of these pedigrees. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation (HSCT) from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment and post-transplantation lymphoproliferative disorder. As acquired trisomy 13 and 21 and FLT3-ITD have all been associated with RUNX1 mutation in sporadic MDS/AML, a combination of single nucleotide polymorphism profiling and mutation analysis was performed to determine whether these secondary genetic events were implicated in the onset of overt malignancy in FPD/AML. Five disease (MDS and/or AML) samples from 4 of our pedigrees with FPD/AML were screened and in all cases, these abnormalities were excluded. Therefore, the secondary mutations that promote MDS/AML in individuals with germline RUNX1 mutations are distinct from those reported in sporadic cases and require further investigation. The small size of modern families and the clinical heterogeneity of the FPD/AML syndrome may have resulted in the diagnosis being previously overlooked. Based on our data, FPD/AML may be more prevalent than previously recognized and therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, particularly prior to consideration of sibling HSCT.

Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4639-4645 ◽  
Author(s):  
Carolyn J. Owen ◽  
Cynthia L. Toze ◽  
Anna Koochin ◽  
Donna L. Forrest ◽  
Clayton A. Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Inherited Mutations ◽  
Runx1 Mutation

Abstract Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germ- line RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment, and posttransplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, before consideration of sibling hematopoietic stem cell transplantation.

Bone Marrow Morphology Associated With GermlineRUNX1Mutations in Patients With Familial Platelet Disorder With Associated Myeloid Malignancy

2019 ◽  
Vol 22 (4) ◽  
pp. 315-328 ◽  
Author(s):  
Karen M Chisholm ◽  
Christopher Denton ◽  
Sioban Keel ◽  
Amy E Geddis ◽  
Min Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Autosomal Dominant ◽  
Germline Mutations ◽  
Thrombocytopenic Purpura ◽  
Myeloid Malignancy ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Runx1 Mutation ◽  
Clonal Abnormalities

Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.

scholarly journals RUNX1 associated Familial Platelet Disorder with Myeloid Malignancy (FPD-MM) in Children: A Novel New Phenotype with Juvenile and Chronic Myelomonocytic Leukemia (JMML/CMML) Characteristics

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5504-5504 ◽  
Author(s):  
Katherine Regling ◽  
Shruti Bagla ◽  
Ahmar Urooj Zaidi ◽  
Erin Wakeling ◽  
Michael C. Chicka ◽  
...  
Keyword(s):  
Chronic Myelomonocytic Leukemia ◽  
Comparative Genomic ◽  
Molecular Testing ◽  
Myeloid Malignancy ◽  
Ras Genes ◽  
Erythroid Hyperplasia ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Myelomonocytic Leukemia ◽  
Runx1 Mutation

Abstract Introduction: RUNX1 (aka AML1; 21q22.12) is indispensable in the establishment of definitive hematopoiesis in humans. Activating RUNX1 mutations are associated with both Acute Myeloid and Lymphoblastic Leukemias (AML, ALL). On the other hand, hypofunctioning RUNX1 mutations cause dominantly inherited Familial Platelet Disorder (FPD). RUNX1 FPD has a high risk for progression to pancytopenia, myeloproliferative disorders (MPD) or AML, hence the new WHO category FPD with myeloid malignancy (FPD-MM). Those with MM carry mutations in other genes seen in AML, MDS. It is a relatively rare disorder with ~75 affected kindreds reported worldwide (Sood, et al. Blood 2017). Detailed reviews of pediatric cases are few. Case Histories: We encountered two children with RUNX1 associated thrombocytopenia; the mutations are novel. The first family is that of 14 yr old AAF, presenting with fainting- blood counts are shown in Table 1; fetal hemoglobin (HbF) was elevated; bone marrow was hypercellular with 6% type 1 blasts, extreme paucity of megakaryocytes, erythroid hyperplasia and large numbers of sea blue histiocytes. The high HbF suggested JMML while the monocyte CD16;14 profile (95.6% CD14+ cells) was similar to that seen in the adult type Chronic Myelomonocytic Leukemia (CMML). Her mother has pancytopenia without excess blasts in the marrow. The second case presented with neonatal thrombocytopenia; father has history of excessive bruising. Results: Blood counts and values for HbF are listed in Table 1. Molecular testing: Case1: A Myeloid gene panel showed RUNX1 - NM_001754.4:c.501delT, p.Ser167Argfs*9; PHF6 - NM_032458.2:c.902dupA, p.Tyr301*; CUX1- NM_001202543.1:c.2378delC, p.Pro793Argfs*26. No mutations were noted in PTPN11, CBL or RAS genes, the latter confirmed by JMML panel done at University of California, San Francisco. UCSF panel identified a mutation in SH2B3, a gene linked to erythrocytosis not caused by JAK2 mutations. Her mother has the same RUNX1 mutation, thus identifying a germline mutation of RUNX1 in her and her child but not the PHF6, CUX1 or the SH2B3 mutations seen in her daughter. A half sibling is unaffected and is a potential transplant donor for the mother. Case2: No coding sequence mutations were detected in genes associated with familial thrombocytopenia including ETV6, GATA1 and RUNX1. Array Comparative Genomic Hybridization studies (Prevention Genetics) identified a heterozygous deletion of the entire exon 5 of RUNX1. To understand the complex findings in family 1 additional studies were done- DRAQ5, CD71, Fetal Hb staining showed that NRBC in Case 1 contained predominantly high HBF cells. LIN28B was markedly elevated in the proband but not the mother (HbF- normal); LIN28B expression was normal in Case 2. Treatment/Outcome: In Case 1, low dose decitabine therapy resulted in the control of MPD features with good Hb recovery and normalization of the monocyte CD16;14 profiles. There was no platelet response to decitabine nor to a course of valproic acid. The child died of fulminant acute graft vs host disease affecting the liver following a 4/6 cord mismatch transplantation. Mother continues to show moderately severe pancytopenia requiring frequent transfusion support. The second child is symptom free with mild thrombocytopenia. Discussion: The hybrid JMML/CMML features in the index child are likely caused by the concurrent CUX1/PHF6/SH2B3 mutations. We are unable to establish if these are true de novo mutations as the father was not available for study; she had no full siblings. Neither high HbF nor high LIN28B are known feature of FPD by itself nor CMML or Polycythemia Vera (p Vera). Recently, the high HbF in JMML has been linked to high expression of LIN28B. SH2B3 mutation may have contributed to the high erythroid proliferation observed in our case. Induced CUX1 haploinsufficiency in mice causes MPD akin to CMML and megakaryocytic (Meg) proliferation (An N, et al. Blood 2018). The virtual absence of Megs in our case indicates that the CUX1 mutation was unable to overcome the Meg ploidization defect caused by the RUNX1 mutation. PHF6 mutations occur in T-ALL and AML but have not been linked to high HbF. Conclusions: Normal HbF and normal LIN28B expression in the mother of Case1 and in Case2 indicate that increased LIN28B is linked to the high HbF in Case 1 and that high LIN28B itself is a consequence of the malignant transformation caused by the concurrent CUX1/PHF6/SH2B3 mutations. Disclosures Chitlur: Baxter, Bayer, Biogen Idec, and Pfizer: Honoraria; Novo Nordisk Inc: Consultancy. Ravindranath:AGIOS: Other: Site Investigator for Pyruvate Kinase Deficiency.

scholarly journals Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation

Haematologica ◽  
2017 ◽  
Vol 102 (10) ◽  
pp. 1661-1670 ◽  
Author(s):  
Rashmi Kanagal-Shamanna ◽  
Sanam Loghavi ◽  
Courtney D. DiNardo ◽  
L. Jeffrey Medeiros ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Malignancy ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Runx1 Mutation

scholarly journals RUNX1 Mutation Leads to Megakaryocyte-Primed Hematopoietic Stem Cell Expansion and Familial Platelet Disorder

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Chen Wang ◽  
Weinan Wang ◽  
Lei Huang ◽  
Yoshihiro Hayashi ◽  
Xiongwei Cai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Platelet Count ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Marker Genes ◽  
Cell Type ◽  
Hematopoietic Stem ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Runx1 Mutation

Backgrounds: Recently it is shown that there exists a subpopulation of hematopoietic stem cells (HSCs) with relatively high expression of VWF and CD41+ at the apex of the hematopoietic stem cell hierarchy. This subset of HSCs, termed mega-HSCs, can give rise to megakaryocytes and platelets directly by bypassing the traditional trajectory of megakaryocyte development from HSC via MPP and MEP. To date, aside from phenotypic marker and transplantation studies, there has been limited understanding of the mechanisms involved in the regulation of mega-HSCs. Runx1 belongs to the RUNT domain transcription factors, and is a key regulator of hematopoiesis especially for the megakaryocyte and platelet differentiation. Loss of RUNX1 in mice causes thrombocytopenia through a blockage of megakaryocyte maturation. One allele RUNX1 loss-of-function mutation is associated with familial platelet disorder (FPD) with a predisposition to developing leukemia. Here we hypothesize that Runx1 plays a role in regulating mega-HSCs to impact on platelet generation, and correcting RUNX1 mutation that causes FPD can therapeutically rescue thrombocytopenia in a mouse model. Methods: We have examined the hematopoiesis and cellularity of various bone marrow (BM) stem/progenitor populations and peripheral blood (PB) in two mouse models. Firstly, conditional knock-out of Runx1flox/flox was mediated by Mx1-Cre upon poly I:C induction. Secondly, the tetracycline-inducible RUNX1 S291fsX300 mutation was knock-in at the collagen a1 locus and the mice was crossed to MLL-PTD knock-in. The mutant RUNX1 is only expressed when the mice are fed with doxycycline and the RUNX1 mutant is "corrected" upon doxycycline withdrawn. In the second model, PB and BM were also tracked after a removal of DOX-induced RUNX1 mutation. The LSK CD150+ HSCs from the mouse BM were isolated by FACS sorting, and 10x Genomics' single-cell RNA-seq (scRNA-seq) analyses were performed to define and track HSPCs. We applied the Louvain algorithm to the scRNA-seq data to identify the cell type clusters and annotated the cell types using the marker genes of each cell cluster. MAST was employed to identify the cell-type specific, differentially expressed genes. Results: In the Runx1 KO mice, two weeks after deletion of Runx1 platelet count showed an ~2-fold decrease to 400~600 k/ul in PB. In the LSK CD150+CD48- or the LSK CD34- FLT3- compartment of BM, the CD41+ mega-HSCs increased ~2-3 fold. In the RUNX1 mutant-on model, mutant mice developed thrombocytopenia 16 weeks after DOX induction with the average platelet count dropping to ~600 k/ul and being maintained at this level. In transplant recipients, the RUNX1 mutant-on mice contained drastically increased mega-HSCs compared with RUNX1 mutant-off mice, synchronous with a decrease of the platelet count in PB. Consistent with these observations, sc-RNAseq data show that in Runx1 KO, among the sequenced LSK CD150+ cells ~70% are HSCs and ~15% are MPP2. Among the HSCs, mega-primed HSCs consist ~33% while non-mega primed HSCs are ~67%. The mega-primed HSCs are distinct by virtual of upregulated platelet-related genes and relative dormant cell cycle status. In the RUNX1 mutant-on model, we found that among the sequenced LSK CD150+ cells ~50% are HSCs and ~12% are MPP2. Interestingly, the mega-primed HSCs are significantly increased in RUNX1 mut-on HSCs compared with mut-off HSCs. Similarly, we saw highly upregulated platelet-driven pathways in mega-HSCs in the mutant-on HSCs. Finally, one month after a withdraw of DOX from the RUNX1 mutant expressing mice when the RUNX1 mutant gene became undetectable, the platelet count returned from ~600 to ~1,000 k/ul in PB, a reversal of the thrombocytopenia phenotype caused by the RUNX1 S291fsX300 expression. Importantly, the correction of Runx1 mutation significantly decreased the proportion of mega-HSCs and restored platelet related pathways in this subset of HSCs. Conclusions: Mega-HSCs contain a high level of platelet-driven gene expression. In addition to its role in regulating the HSC-MPP-MEP mediated megakaryocyte development, RUNX1 is important in regulating mega-HSCs by maintaining proper expression of mega-platelet leaning genes. Correction of RUNX1 mutation that causes FPD can rescue mega-HSC population and revert FPD, providing a rationale for future treatment strategies by gene editing in RUNX1 mutation bearing FPD patients. Disclosures No relevant conflicts of interest to declare.

RUNX1 Mutations in Acute Myeloid Leukemia (AML): Correlation with Distinct Cytogenetic Subgroups and Clinical Outcome. Results of the AML Study Group (AMLSG)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 145-145 ◽  
Author(s):  
Verena I. Gaidzik ◽  
Richard F. Schlenk ◽  
Kerstin Wittke ◽  
Annegret Becker ◽  
Andreas Zimmermann ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mutation Screening ◽  
Trisomy 13 ◽  
Trisomy 8 ◽  
Hematopoietic Stem ◽  
Platelet Disorder ◽  
De Novo Aml ◽  
Runx1 Mutation

Abstract Background: The runt-related transcription factor 1 (RUNX1) gene encodes a transcription factor that is required for hematopoietic stem cell emergence during development and that functions as a key regulator of hematopoiesis at several steps. Mutations in RUNX1 have been identified in sporadic myeloid leukemia through translocations [e.g., RUNX1-RUNX1T1 in t(8;21) or RUNX1-EVI1 in t(3;21)], point mutations or amplifications. In addition, germline mutations in RUNX1 result in familial platelet disorder with propensity for the development of myeloid leukemia. More recent data suggest that RUNX1 mutations are not strongly associated with MDS, secondary AML (s-AML) or therapy-related AML (t-AML) but seem to be more related to distinct cytogenetic subgroups such as trisomy 13, trisomy 21, loss of 7q, and trisomy 8. Aims: To evaluate the incidence and clinical impact of RUNX1 mutations in a large cohort of younger (16 to 60 years of age) adult AML patients who were entered on AMLSG treatment protocol AML HD98A. Methods: RUNX1 mutation screening was performed in 349 consecutive AML patients (de novo AML, n=282; s-AML, n=49; t-AML, n=18) using a DNA-based PCR assay for amplification of exons 1 to 8 followed by direct sequencing. The only criterion to include patients was the availability of a bone marrow or peripheral blood sample from diagnosis for gene mutation analysis. Results: RUNX1 mutations were identified in 32 of 349 (9.2%) AML; mutations clustered in exon 3 (11/32) and exon 8 (11/32), but also occurred in other regions of the gene (10/32). With regard to cytogenetic subgroups, the incidence of RUNX1 mutations was 9.7% (20/206) in AML with normal karyotype, 8.3% (3/36) in core-binding factor leukemia, 14.2% (4/28) in various cytogenetic abnormalites including trisomy 8 in three cases, 7.6% (2/26) in AML with high-risk aberrations, whereas only 1 of 8 pts with t(11q23) and none of 29 cases with t(15;17) leukemia revealed a RUNX1 mutation; in 2 of 16 cases cytogenetics was not available. RUNX1 mutations were significantly associated with MLL-PTD (p=0.003), whereas concurrent NPM1 mutations were less frequent in the RUNX1 mutated group (p=0.0002); there was no association of RUNX1 mutations with FLT3-ITD/TKD, CEBPA, RAS and WT1 mutations. There were no differences in patients characteristics such as age, WBC counts, LDH levels, platelet counts, and distribution of de novo AML, s-AML, and t-AML between the RUNX1 mutated and RUNX1 wildtype group. Compared to RUNX1 wildtype AML, those with RUNX1 mutations had a significantly higher rate of resistant disease following induction therapy (38% and 20%, respectively; p=0.03) which translated into a significantly inferior event-free survival (p=0.004). There was no difference in relapse-free and overall survival between the two groups. Conclusions: In younger adult patients with AML, RUNX1 mutations are found in approximately 10% of cases and are associated with cytogenetic subgroups. RUNX1 mutations appear to be associated with a higher rate of induction failure.

Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3565-3572 ◽  
Author(s):  
Weili Sun ◽  
James R. Downing
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Normal Limits ◽  
Platelet Disorder ◽  
Familial Platelet Disorder ◽  
Transcriptional Complex

The AML1/CBFβ transcriptional complex is essential for the formation of definitive hematopoietic stem cells (HSCs). Moreover, development of the hematopoietic system is exquisitely sensitive to the level of this complex. To investigate the effect of AML1 dosage on adult hematopoiesis, we compared the hematopoietic systems of AML1+/– and AML1+/+ mice. Surprisingly, loss of a single AML1 allele resulted in a 50% reduction in long-term repopulating hematopoietic stem cells (LTR-HSCs). This decrease did not, however, extend to the next level of hematopoietic differentiation. Instead, AML1+/– mice had an increase in multilineage progenitors, an expansion that resulted in enhanced engraftment following transplantation. The expanded pool of AML1+/– progenitors remained responsive to homeostatic mechanisms and thus the number of mature cells in most lineages remained within normal limits. Two notable exceptions were a decrease in CD4+ T cells, leading to an inversion of the CD4+ to CD8+ T-cell ratio and a decrease in circulating platelets. These data demonstrate a dosage-dependent role for AML1/CBFβ in regulating the quantity of HSCs and their downstream committed progenitors, as well as a more restricted role in T cells and platelets. The latter defect mimics one of the key abnormalities in human patients with the familial platelet disorder resulting from AML1 haploinsufficiency.

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