Therapy-Related Hematopoietic Neoplasia

2020-11-01   Mark A Micale 

1.Departments of Pathology and Laboratory Medicine and Obstetrics & Gynecology Beaumont Health and Oakland University William Beaumont School of Medicine 3601 West Thirteen Mile Rd. Royal Oak, MI 48073 mmicale@beaumont.edu

Abstract

Despite new treatments for solid tumors and hematolymphoid malignancies, including targeted therapy and immunotherapy, many cancer patients still require more traditional therapies utilizing cytotoxic chemotherapy and conventional ionizing radiation. These treatments can result in significant short-term morbidity and long-term problems, most notably the development of a therapy-related hematopoietic neoplasm. Therapy-related malignancies usually have a poor outcome, and because of this, there is an effort to elucidate the genetic, molecular, and environmental etiology of these diseases. In this paper, the latest research focused on characterizing therapy-related hematopoietic neoplasms and their pathogenetic mechanisms will be presented along with a compilation of the most common cytogenetic and molecular changes associated with these conditions.

Clinics and Pathology

Etiology

A late-term complication of cytotoxic chemotherapy and radiotherapy for the treatment of both malignant and non-malignant conditions is the development of a therapy-related hematopoietic neoplasm. The World Health Organizations (WHO) most recent Classification of Tumors of Hematopoietic and Lymphoid Tissues (2017) recognizes the entity Therapy-Related Myeloid Malignancies to include therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) [Vardiman et al, 2017]. While not currently recognized as a specific WHO entity due to the small number of cases, several recent studies have begun to characterize therapy-related acute lymphoblastic leukemia (t-ALL) as well [Aldoss et al, 2018; Aldoss et al, 2019; Saygin et al, 2019]. For therapy-related myeloid neoplasms (t-MN), the latency period from original diagnosis to development of neoplasia is dependent upon the nature of the primary exposure. For patients that have received radiation or alkylating agent chemotherapy (including classical agents such as cyclophosphamide, alkylating-like agents such as the platinum-based drugs, or nonclassical agents like procarbizine), the latency period is on average five years and is characterized by cytogenetic abnormalities involving chromosomes 5 [ monosomy 5/del(5q)] and 7 [ monosomy 7/del(7q)]. These patients often develop MDS first, which is difficult to treat and quickly progresses to AML with multilineage dysplasia, and is therefore associated with a poor prognosis. The second subtype of t-MN results from exposure to topoisomerase II inhibitors such as irinotecan, doxorubicin, or etoposide. These neoplasms have a shorter latency period, on average 1-2 years, present as AML without a preceding MDS, are associated with rearrangement of the KMT2A (MLL) gene at chromosome 11q23 or RUNX1 (AML1) gene at 21q22.1, and have a more favorable outcome with intensive induction therapy compared with their alkylating-agent counterpart [Churpek et al, 2013; McNerney et al, 2017].
Therapy-related acute lymphoblastic leukemia (t-ALL) is less well characterized than its myeloid counterpart and has a longer latency period (median 7 years) except for those with KMT2A rearrangement, but is otherwise similar in presentation including prior exposure to both cytotoxic and topoisomerase II inhibitors, similar abnormalities of chromosomes 5 and 7, and an inferior outcome [Aldoss et al, 2018].

Epidemiology

Therapy-related myeloid neoplasms account for 10-20% of all cases of myeloid malignancy (AML, MDS, and MDS/MPN). In this group, more patients received prior treatment for a solid tumor (70%) versus a hematopoietic neoplasm (30%). While breast and hematolymphoid malignancies (including Hodgkin and non-Hodgkin lymphoma as well as plasma cell myeloma) account for the largest number of primary diagnoses, treatment for most tumors carries a risk of t-MN. Treatments for solid tumors that utilize either alkylating agents, topoisomerase II inhibitors, or platinum at high doses, including bone / soft tissue, testicular, anal, ovarian /gynecological, and brain malignancies, as well as breast, are at highest risk of developing a t-MN [Murthy and Abedin, 2019]. While any age-group can be affected, the incidence of t-MN mirrors the increased risk of malignancy associated with increasing age, with a median age at diagnosis of 64 years, comparable to de novo AML. Adjusting for confounding variables such as high-risk karyotypes, comorbidities, and poor performance status, a study by Granfeldt Ostgard and colleagues (2015) found that t-MN patients 60 years and older had a similar outcome as patients with de novo disease, suggesting that the two diseases may be biologically similar in older patients; however, in younger patients, t-MN should be considered an independent poor prognostic factor.
With better treatments for cancer, survival rates among many cancers is increasing; however, this will likely result in an increased incidence of t-MN as a long-term complication of this success. Presently, chemotherapy increases the risk of t-MN by 4.7-fold as does younger age at the time of exposure. For breast cancer, the use of hematopoietic growth factors, specifically GSF3 (granulocyte colony-stimulating factor G-CSF) to support blood count recovery also increases the relative risk of t-MN. Changes in treatment protocols have led to changes in incidence of t-MN. For Hodgkin lymphoma, the historical treatment plan included alkylating agent-based chemotherapy with or without extended field radiotherapy, resulting in a 2-6.7% incidence of t-MN, with higher rates if maintenance oral-alkylating agent therapy is utilized; however, with modern therapy protocols including limited radiation, the incidence of t-MN has fallen to 0-0.03% after ten year follow-up. In contrast, risk of t-MN has increased for non-Hodgkin lymphoma, especially following allogenic hematopoietic stem cell transplantation [Churpek et al, 2013; McNerney et al, 2017; Vardiman et al, 2017]. Therapy- related myeloid disorders can also occur as the result of treatments for non-malignant conditions such as autoimmune diseases [Zhang and Wang, 2014], after solid organ transplantation [Dharnidharka 2018], and following autologous or allogenic stem cell transplantation for either malignant or non-malignant conditions [Danylesko and Shimoni, 2018; Saygin et al, 2019].
Therapy-related acute lymphoblastic leukemia (t-ALL) is relatively rare, and for this reason has not been well characterized nor is it a recognized WHO entity in the latest revision. When compared with de novo ALL, t-ALL patients are generally older and more often female. Agents used for immunosuppression to treat autoimmune diseases such as rheumatoid arthritis and following solid organ transplantation and stem cell transplantation also increase the risk of therapy-related lymphoproliferations such as lymphoma [Bagg A, 2011; Aldoss I et al, 2018].
T-ALL has not been as well characterized as its myeloid counterpart because of the lack of large data sets, and so, unlike t-MN, t-ALL is not yet considered a specific entity in the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue. The frequency of t-ALL is reported to be 3-9% of all adult ALL cases, compared with 10-20% t-MN among all myeloid neoplasms. As with t-MN, the prognosis of t-ALL is significantly worse than in de novo ALL. Comparable is the latency period from cytotoxic therapy to development of t-ALL, with a shorter period associated with topoisomerase II inhibitors and KMT2A rearrangement as compared with other chemotherapy and radiation. The most common primary malignancies associated with t-ALL include breast cancer (26%), plasma cell myeloma (19%), prostate cancer (13%), and non-Hodgkin lymphoma (11%) [Saygin et al, 2019]. The incidence of t-ALL appears to be higher in females, likely due to the high incidence of breast cancer and the multimodality treatment such patients receive, including chemotherapy, adjuvant chemotherapy, and radiation, resulting in long term survival for many.
Because fewer cases of t-ALL have been reported, no large-scale studies examining the pathogenesis of the disease have been published; however, the causes of t-ALL are thought to be like those of t-MN. The majority of cases are believed to be due, in large part, to prior cytotoxic therapy for a primary malignancy which results in DNA damage. Likely also contributing to the pathogenesis of t-ALL, like t-MN, is inherited predisposition to mutations in DNA repair genes such as BRCA1, BRCA2, TP53, CHEK2, and PALB2. There are also ALL patients with a prior malignancy but without any cytotoxic therapy, suggesting the possibility of two primary malignancies without inherited predisposition [Aldos et al, 2019].

Pathology

Genomic mechanisms that are associated with development of t-MN are not mutually exclusive, and more than one pathway may contribute to t-MN. These include inherited predisposition as well as chemotherapy and/or radiation induced: 1) cytogenetic abnormalities, 2) somatic gene abnormalities, 3) clonal selection, and 4) damage to bone marrow microenvironment:

Other features

Damage to Bone Marrow Microenvironment. There is growing evidence that alteration of the bone marrow microenvironment (niche) contributes to the development of myeloid malignancies. Bidirectional crosstalk between HSCs and the niche, which includes mesenchymal stromal cells (MSCs) and progeny cells derived from MSCs such as osteoblasts, has been uncovered in recent studies. Aberrant differentiation of MSCs as well as alterations in key signalling pathways within the bone marrow niche, including WNT-β catenin ( CTNNB1) and NOTCH, have been observed in myeloid malignancies. For example, multiple studies using gene expression profiling demonstrated activation of the WNT pathway in MDS, AML, and t-MN positive for the del(5q) chromosome. Canonical WNT signalling is responsible, in part, for regulating hematopoiesis and maintaining bone marrow niche function. Dysregulating the WNT- β-catenin pathway has been correlated with genomic instability and the presence of complex karyotypes [McNerney et al, 2017]. Another study found that in 38% of patients with AML and MDS, most of whom had del(5q)/monosomy 5 and/or del(7q)/monosomy 7, activation of β-catenin in bone marrow osteoblast cells with subsequent increase in NOTCH signalling in HSCs occurred [Kode A et al, 2014].
The effects of cytotoxic therapy on the bone marrow niche are complex and not completely understood, but have been shown to include a pro-inflammatory response with release of cytokines, damage to HSCs by reactive oxygen species released by multipotent stem cells, and remodelling of the bone marrow niche. Studies in both mice and humans have demonstrated that such exposure to cytotoxic agents creates a "malignant" bone marrow microenvironment that supports selection of mutant HSCs at the expense of healthy HSCs. These mutant stem cells often have reduced TP53 function and apoptosis. Clonal expansion then results in a therapy-related malignancy which, not surprisingly, is difficult to treat. [McNerney et al, 2017].

Cytogenetics

One of the major pathogenetic mechanisms underlying the development of t-MN is the acquisition of chromosome abnormalities, found in up to 95% of patients. Approximately 70% of these patients possess an unbalanced karyotype while the remaining 30% present a balanced rearrangement(s) [Vardiman et al, 2017]. The abnormalities are similar to those found in de novo disease; however, t-MN is enriched for high-risk cytogenetic markers. The most common unbalanced rearrangements in t-MN involve deletion of a contiguous chromosome region (CCR) on either chromosome 5q or 7q, whereby the genes within the CCR are functionally unrelated but usually deleted as a block. Constitutional examples of such genomic rearrangements include DiGeorge, Williams, and Prader Willi /Angelman syndromes, whereby a single gene in the CCR may be critical, yet deletion of the entire block of genes within the affected chromosome segment is required for the complete phenotype. In myeloid malignancy, efforts to identify a single critical gene within these commonly deleted regions have been generally unsuccessful, because it appears that there may be a number of genes within the deleted regions responsible for the morphological phenotype. While tumor suppressor genes within these regions appear to be haploinsufficient, precluding identification of a second inactivating mutation, minimally deleted region (MDR) mapping has been possible. An MDR on chromosome 5q31.2 is observed in t-MN, de novo AML, and high-risk MDS while an MDR on chromosome 5q32 is associated with the isolated del(5q) in MDS. A large segment of chromosome 5q spanning the breakpoints 5q14 and 5q33 contains 17 genes, including the APC gene which encodes components of the WNT signalling pathway critical for hematopoiesis and leukemogenesis [McNerney et al, 2017]. Other studies have elucidated the role of deletion of chromosome 5q genes in MDS, including RPS14 associated with the anemia observed in del(5q) MDS [Ebert el al, 2008] and Fli1 associated with thrombocytosis [Neuwirtova et al, 2013]. Stengel et al (2016) found that larger chromosome 5q deletions are associated with TP53 gene mutations as well as additional chromosome abnormalities often as part of a complex karyotype (>3 chromosome abnormalities). These include del(3p), gain of chromosome 8, del(11q), del(13q), del(17p)/monosomy 17, loss of chromosomes 18 and 21, and del(20q) [Vardiman et al, 2017]. Loss of TP53 occurring with del(17p)/monosomy 17 generates greater genomic instability resulting in additional chromosome abnormalities. It also appears that the evolution of pre-existing or emerging subclones with TP53 mutation is a good predictor of disease progression in low-risk del(5q) [Lode et al, 2018].
Chromosome 7q contains three MDRs at 7q22, 7q34, and 7q35-q36. Important genes in these regions include the tumor suppressor gene cut-like homeobox 1 (CUX1) at 7q22; pre-mRNA splicing factor LUC7 like 2 (LUC7L2) gene on 7q34; and KMT2C (MLL3) tumor suppressor, enhancer of zeste homolog 2 (EZH2), and cullin 1 (CUL1) genes at 7q35-q36. In addition, an inherited mutation of the sterile alpha motif domain containing protein 9 like (SAMD9L) gene on 7q21.2 predisposes to AML with monosomy 7 [McNerney et al, 2017].
Thirty percent of t-MN patients present balanced chromosome rearrangements, with 10-15% of these cases demonstrating favorable-risk cytogenetic markers t(8;21)(q22;q22), t(15;17) (q22;q21), and less commonly inv(16)(p13q22). In t-MN, while the prognosis associated with these favorable-risk abnormalities is not as good as in de novo AML, it is better than that associated with high-risk markers including del(5q)/monosomy 5, del(7q)/monosomy 7, complex karyotypes, and TP53 gene deletion/mutation. Normal karyotypes are also found in t-MN, although at a lower frequency compared with de novo AML [Vardiman et al, 2017]. Samra et al (2020) explored the prognostic significance of a normal karyotype in t-AML and found that it was associated with an inferior outcome compared with de novo AML; however, this appeared to be largely due to an increased risk of death in remission as opposed to differences in molecular features or relapse risk. Kim et al (2018) found that t-MN patients with a normal karyotype demonstrated better overall survival after allogenic stem cell transplantation compared with patients that possessed other intermediate-risk markers.

Genes

Somatic Gene Alterations. Studies have revealed an overlap in t-MN and de novo AML involving the most commonly mutated genes in these two conditions and the pathways/key cellular components these genes code for or regulate, including chromatin modification, transcription factors, signalling proteins, and the spliceosomal complex. Our understanding of the somatic gene alterations that contribute to t-MN has increased through utilization of next generation sequencing (NGS). Wong et al (2015) studied the whole genomes of 22 t-MN patients along with 149 AML and MDS-related genes in another 89 patients. Contrary to their hypothesis that a greater number of somatic mutations would be found in t-MN compared with de novo AML owing to DNA damage resulting from chemotherapy and radiation therapy, they found a similar number of single nucleotide variants, indels, and copy number alterations in both patient groups. The conclusion from this study and that of Ok CY et al (2015) is that treatment-induced DNA damage is not the only or major driver of t-MN.
In the study by Ok and colleagues (2015), distinct differences between de novo MN and t-MN included the higher incidence of mutations in TP53, KIT, WT1, PTPN11, IDH1/2, and EZH2 genes in t-MN, with de novo disease demonstrating a greater number of mutations in NPM1 and FLT3. [Ok CY et al, 2015; Vardiman et al, 2016]. Singhal et al (2019) compared the clinical and mutational characteristics of t-MN and primary MDS and found both similarities and differences in mutational signatures as well as clinical outcomes between t-MN and primary MDS. While the mutation frequency was found to be similar between the two entities, the mutation pattern was different, with TP53 and SRSF2 mutations more frequent in t-MN possibly due to clonal selection and expansion of hematopoietic stem cells with these mutations under genotoxic stress.
Kuzmanovic and colleagues (2019) described two genetic pathways leading to t-MN, one with mutation of the TP53 gene occurring in up to 37% of t-MN and the other associated with chromosome 7 abnormalities and activation of the RAS pathway. Both t-MN and de novo AML with mutated TP53 as the initiating event in many cases, often present the del(5q) chromosome/monosomy 5 (often as part of a complex karyotype) and predict a poorer outcome. [McNerney et al, 2017]. Unlike in primary disease where most TP53 mutations occur in the DNA binding domain, those identified in t-MN are often associated with nuclear trafficking. Sometimes, acquisition of a TP53 mutation occurs as a secondary event, predicting a high likelihood of leukemic transformation. The second genetic pathway in t-MN, occurring in 49% of patients with a poor outcome, involves del(7q) chromosome/monosomy 7 and mutation of a gene that results in activation of the RAS pathway. Monosomy 7/del(7q) can also be observed with del(5q)/monosomy 5 in some cases of t-MN, often as part of a complex karyotype [McNerney et al, 2017].
Clonal Selection. The concept of clonal hematopoiesis of indeterminate potential (CHIP) is a relatively new one, described by Steensma et al in 2015 as the presence of neoplasia-related mutation(s) in a population of hematopoietic cells without morphological evidence of bone marrow disease. While almost 1% of healthy middle-aged individuals are found to carry a clonal molecular or cytogenetic abnormality, that figure increases in people 50-70 years old, with clonal expansion occurring over time. In one study utilizing error-corrected sequencing (which enables the accurate detection of clonal mutations as rare as 0.0003 variant allele frequency), CHIP was identified in 95% (19/20) of healthy individuals aged 50-60 years [Young et al, 2016]. Mutations commonly identified in CHIP are also found in AML, including in epigenetic modifying genes such as DNMT3A, ASXL1, and TET2, along with TP53. Common cytogenetic abnormalities found in patients with CHIP are recurrent cytogenetic markers in myeloid neoplasia as well, including del(11q), del(13q), del(20q), and trisomy 8. Not surprisingly, these individuals have an increased lifetime risk of developing a hematological malignancy. There is now strong evidence that some patients with a t-MN possess a pre-existing (before chemotherapy or radiation) mutation(s) in hematopoietic stem cells (HSCs). Such cells, under the stress of chemotherapy or radiation may be selected for in the pool of both normal and mutant HSCs so that they predominately repopulate the bone marrow over time. Having been selected for their increased fitness under genotoxic stress, neoplastic cells in t-MN are resistant to treatment [McNerney et al, 2017]. Certain mutations identified in CHIP, such as DNMT3A and TET2, are also observed in MDS patients, suggesting that CHIP progresses to MDS in some individuals [Katagiri et al, 2019]. The study by Kuzmanovic and colleagues revealed evidence that approximately half of TP53-mutated t-MN may be CHIP-related, with cytotoxic therapies accelerating the progression from CHIP to t-MN. They also identified a two-fold increase in TP53 double mutants in t-MN versus in primary myeloid neoplasia [Kuzmanovic et al, 2020]. Soerensen et al (2020) demonstrated that there may be value in evaluating for clonal hematopoiesis in stem cells harvested at leukophoresis [prior to autologous stem cell transplant (ASCT)] using a myeloid NGS panel. Their study demonstrated that identification of low variant allele frequencies, along with aberrant CD7 expression in patients with primary non-myeloid malignancy may indicate an increased risk of developing tMN after ASCT.

Prognosis

Patients with t-AML that present with favorable cytogenetic markers including t(8;21), inv(16), and t(15;17) can be treated in the same way as those with de novo disease. Intensive induction chemotherapy with the 7+3 regimen followed by consolidation chemotherapy has been the mainstay; however, a newer treatment for induction called CPX-351 (Vyxeos) has been used. CPX-351 is a liposomal encapsulation of daunorubicin and cytarabine in a 1:5 molar ratio. The results of initial studies revealed an increased overall survival in those patients receiving CPX-351 compared to standard 7+3 therapy. CPX-351 is then used in consolidation after remission. For patients who cannot undergo intensive chemotherapy, Venetoclax with hypomethylating agents or low-dose cytarabine have been used in clinical trials. For patients with intermediate-risk cytogenetic markers, intensive or low-intensity chemotherapy followed by hematopoietic stem cell transplant (HSCT) is recommended. In fact, HCST is regarded as the only curative treatment for t-AML, with better overall survival than consolidation chemotherapy. For unfavorable risk cytogenetic markers, including TP53 mutations, t-MN patients should be referred for a clinical trial or HSCT, if possible [Dhakal et al, 2020]. It has been suggested that restoration of a more normal hematopoietic stem cell microenvironment by reducing the inflammation in bone marrow brought on by cytotoxic therapies might alter therapy-related clonal hematopoiesis [Park and Bejar, 2020].

Note

Inherited Predisposition. NGS studies have identified an inherited mutation in a cancer-associated gene in 8.5-12.6% of cancer patients compared with an incidence of 1-2.7% in patients without known cancer [McNerney et al, 2017]. In addition, while many patients with similar primary malignancies and cytotoxic exposures develop a therapy-related neoplasm, some do not. This phenomenon may, at least in part, be explained by the presence of germline DNA variants in genes for detoxification of chemotherapeutic drugs such as GSTP1 and NQ01, as well as genes that function to repair DNA damage, maintain genomic stability, regulate the cell cycle, and control apoptosis. Such variants may increase the susceptibility to develop a therapy-related neoplasm after cytotoxic drug or radiation exposure. Several studies found that breast cancer survivors with t-MN had germline mutations in DNA-damage response genes including BRCA1, BRCA2, TP53, CHEK2, PALB2, and BARD1 [Schulz et al, 2012; Churpek et al, 2016]. The revised WHO Classification also includes an entity for myeloid neoplasms with germline mutations in DDX41 and ANKRD26 genes. It should be noted that second hematopoietic malignancies that occur after the common latency period following cytotoxic therapy may, in fact, not be "therapy-related", but may represent a second primary malignancy due in part to genetic susceptibility [Chua CC et al, 2019; Takahashi K, 2019].
Autoimmune diseases (AD) including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disorders, multiple sclerosis, ankylosing spondylitis, and others are associated not only with an increased risk of lymphoproliferative disorders but myeloid malignancies as well. In a SEER population-based study, a significantly increased risk of either AML or MDS of 1.29 and 1.5, respectively, was found in patients with an AD [Anderson et al, 2009]. The risk of developing a myeloid neoplasm in an AD appears to be based on several factors including shared genetic susceptibilities with polymorphisms in DNA-repair and drug metabolizing genes, treatment exposure (especially to thiopurines, alkylating agents, and topoisomerase inhibitors), chronic bone marrow stimulation, and immune surveillance defects. In addition, rheumatic disease may co-occur with or be a prelude to an underlying hematological malignancy. It should be kept in mind, however, that not all myeloid malignancies that appear in patients with AD are "therapy-related" as some myeloid neoplasms appear in certain AD subtypes in the absence of prior therapy [Boddu et al, 2019].

Cytogenetics

Atlas Image
This bone marrow karyogram is from a 45-year old women with anemia and thrombocytopenia. She is s/p chemotherapy including etoposide for lung cancer completed 34 months ago. Based on these findings and those of morphological and flow cytometric evaluation, the patient was diagnosed with t-AML. The karyotype is: 46,XX,t(16;21)(q24;q22).

Cytogenetics morphological

ETV6 gene (12p13) rearrangements:
- t(4;12)(q12;p13) CHIC2 /ETV6: t-AML and t-ALL; B-cell ALL cases seem to have a more distal breakpoint in 4q13 or 4q21; Median survival is poor, possibly one year.
-t(7;12)(p15;p13), t(12;20)(p13;q11)
- t(12;22)(p13;q12) ETV6/ MN1: t-MN; Survival not certain due to small number of cases, but of nine reported, the survival range was up to 6 years with a median of 2 years.
KMT2A (formally MLL) gene (11q23) rearrangements: t-AML, t-ALL, and biphenotypic acute leukemia; found mainly following treatment with topoisomerase II inhibitors; prior malignancy is variable; prognosis is poor.
- inv(11)(q21q23) KMT2A/ MAML2
- t(1;11)(p32;q23) EPS15 /KMT2A
- t(1;11)(q21;q23) MLLT11 /KMT2A
- t(4;11)(q21;q23) AFF1 /KMT2A
- t(6;11)(q27;q23) AFDN /KMT2A
- t(9;11)(p22;q23) MLLT3 /KMT2A
- t(10;11)(p12;q23) MLLT10 /KMT2A
- t(11;16)(q23;p13.3) KMT2A/ CREBBP
- t(11;17)(q23;q25) KMT2A/ SEPT9
- t(11;19)(q23;p13.3) KMT2A/ MLLT1
- t(11;19)(q23;p13.1) KMT2A/ ELL
RUNX1 (formally AML1) gene (21q22) rearrangements:
- t(8;21)(q22;q22) RUNX1T1 / RUNX1: t-MDS or t-AML; Primary malignancy is solid tumor in 70% of cases; Median survival is 17 months with additional abnormalities and 31 months without additional abnormalities.
- t(3;21)(q26;q22) MECOM /RUNX1: t-MDS and t-AML; Median survival is 8 months.
- t(16;21)(q24;q22) CBFA2T3 /RUNX1: t-AML; Median survival is poor.
RPN1 /MECOM (3q21q26) gene rearrangement:
- inv(3)(q21q26) and t(3;3)(q21;q26): t-MDS or t-AML; primary malignancy is solid tumor in half of cases; Median survival is very poor (7 months).
NUP98 gene (11p15) rearrangements:
- inv(11)(p15q22) and t(11;11)(p15;q22); NUP98/ DDX10: t-MDS and t-AML
- t(7;11)(p15;p15) NUP98/ HOXA9
dic(1;7)(q10;p10) Results in 1q trisomy and 7q monosomy; Half of cases after chemotherapy and radiation; Usually found as the sole abnormality; Breakpoints within α-satellite DNA; Has a distinct gene expression profile associated with gene downregulation supported by a specific epigenetic profile [Fernandez et al, 2019].
t(3;8)(q26.2;q24) MECOM/ MYC rearrangement: Shares similarities with inv(3) GATA2 /MECOM; Dismal outcome.
t(8;16)(p11.2;p13.3) KAT6A / CREBBP rearrangement: Median survival is very poor (5 months); Associated with hemophagocytosis [Xie et al, 2019].
t(9;22)(q34;q11.2) BCR / ABL1 rearrangement: t-AML and t-ALL; primary malignancy is solid tumor in 70% of cases; Median survival is very poor (5 months).
t(15;17)(q22;q21) PML / RARA rearrangement: t-MDS and t-AML; Primary disease is solid tumor in 70% of cases; Median survival is 29 months, although some studies have reported comparable outcomes to de novo acute promyelocytic leukemia [Dhakal et al, 2020].
inv(16)(p13q22) CBFB / MYH11 rearrangement: t-MDS and t-AML; Primary malignancy is solid tumor in 70% of cases; Patients under 55 years appear to have better outcomes; Median survival is 29 months with 45% of patients alive at 5 years (the best survival among subgroups of treatment-related hematopoietic neoplasms with a balanced chromosome rearrangement).
Cytogenetic abnormalities identified in t-ALL are often similar to those observed in t-MN, including monosomal karyotypes; del(5q) and del(7q) chromosomes; KMT2A gene rearrangements; and mutations in genes including DNMT3A, RUNX1, and ASXL1; however, some patients present mutations in genes primarily associated with ALL including CDKN2A IKZF1, FANCL, FANCD2, and BRCA2. The study by Saygin et al, 2019 evaluated patients with t-ALL, de novo ALL (dnALL), and ALL with a prior malignancy but with no history of cytotoxic therapy (pmALL). They found different cytogenetic profiles in t-ALL compared with dnALL and pmALL, with a higher incidence of KMT2A rearrangement (13%) in the t-ALL group compared with 8% in the dnALL group and no cases in the pmALL patients. In addition, 27% of t-ALL patients demonstrated MDS-associated chromosome abnormalities including deletion of chromosomes 5q, 7q, 11q, 13q, 17p, and 20q, along with trisomy 8. By comparison, only 7% of dnALL cases and no cases of pmALL revealed such abnormalities. The t(9;22)(q34;q11.2), the most common abnormality found in adults with de novo ALL, is commonly found in adults with t-ALL as well; however, curiously, 21% of pediatric t-ALL cases in one study presented the Philadelphia chromosome, which is a much higher frequency than what is observed in dnALL in this age group (3%). Cases with the t(9;22) also presented additional chromosome abnormalities at a higher than expected frequency, possibly due to the genetic instability created by prior therapy [Aldoss et al, 2019].
Atlas Image
This bone marrow karyogram is from an 84-year old women with macrocytic anemia. She is s/p chemotherapy for breast cancer completed 49 months ago. Based on these findings and those of morphological and flow cytometric evaluation, the patient was diagnosed with t-MDS. The karyotype is: 46,XX,inv(3)(q21q26).

Genes Involved and Proteins

Gene name
ANKRD26 (Ankyrin repeat domain 26)
Location
10p12.1
Protein description
This gene encodes a protein containing N-terminal ankyrin repeats that function in protein-protein interactions.
Gene name
EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit)
Location
7q36.1
Protein description
This gene encodes a member of the Polycomb-group (PcG) family and may play a role in the hematopoietic and central nervous systems. PcG family members form multimeric protein complexes which are involved in maintaining the transcriptional repressive state of genes over successive cell generations.
Gene name
FANCD2 (FA complementation group D2)
Location
3p25.3
Protein description
This gene encodes a ubiquitin ligase protein that is a member of the Fanconi anemia complementation group (FANC), specifically the protein for complementation group D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 and BRCA2) involved in homology-directed DNA repair.
Gene name
FANCL (FA complementation group L)
Location
2p16.1
Protein description
This gene encodes a ubiquitin ligase protein that is a member of the Fanconi anemia complementation group (FANC), specifically the protein for complementation group L that mediates monoubiquitination of FANCD2 and FANCI.
Gene name
FLI1 (FLi1 proto-oncogene, ETS transcription factor)
Location
11q24.3
Protein description
This gene encodes a transcription factor containing an ETS DNA-binding domain.
Gene name
FLT3 (Fms related receptor tyrosine kinase 3)
Location
13q12.2
Protein description
This gene encodes a receptor tyrosine kinase that regulates hematopoiesis. The receptor is activated by binding of the fms-related tyrosine kinase 3 ligand which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. This phorylation activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow.
Gene name
GSTP1 (Glutathione S-transferase Pi 1)
Location
11q13.2
Protein description
Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. The protein encoded by this gene is thought to play a role in xenobiotic metabolism and to play a role in susceptibility to cancer.
Gene name
IDH1 (Isocitrate dehydrogenase 1) and IDH2 (Isocitrate dehydrogenase 2)
Location
IDH1-2q34, IDH2-15q26.1
Protein description
The proteins encoded by these genes are the NADP(+)-dependent isocitrate dehydrogenases found in cytoplasm and peroxisomes. They catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate and so play a role in metabolism and energy production.
Gene name
IKZF1 (IKAROS family zinc finger 1)
Location
7p12.2
Protein description
This gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The expression of this protein is restricted to fetal and adult hemo-lymphopoietic system, and it functions as a regulator of lymphocyte differentiation.
Gene name
KIT (KIT proto-oncogene, receptor tyrosine kinase)
Location
4q12
Protein description
This gene encodes the human homolog of the proto-oncogene C-KIT which was originally identified as the cellular homolog of the feline sarcoma viral oncogene v-kit. This tyrosine-protein kinase acts as a cell-surface receptor for the cytokine KITLG (SCF) and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways.
Gene name
KMT2A (Lysine methyltransferase 2A; mixed lineage leukemia) (MLL)
Location
11q23.3
Protein description
This gene encodes a transcriptional coactivator protein that plays an essential role in regulating gene expression during early development and hematopoiesis. One of its conserved domains, SET, is responsible for histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation.
Gene name
KMT2C (lysine methyltransferase 2C) (MLL3)
Location
7q36.1
Protein description
This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein which is a member of the NCOA6 (ASC-2) complex (ASCOM) that possesses histone methylation activity and is involved in transcriptional coactivation.
Novo
methylation, rather then in maintenance methylation.
Gene name
LUC7L2 (LUC7 like 2, pre-mRNA splicing factor)
Location
7q34
Protein description
The protein encoded by this gene may be involved in the recognition of non-consensus splice donor sites in association with the U1 snRNP spliceosomal subunit.
Gene name
NPM1 (Nucleophosmin 1)
Location
5q35.1
Protein description
The protein encoded by this gene is involved in centrosome duplication, protein chaperoning, and cell proliferation. It shuttles between the nucleolus, nucleus, and cytoplasm to chaperone ribosomal proteins and core histones from the nucleus to the cytoplasm. It also sequesters the tumor suppressor ARF in the nucleolus, protecting it from degradation until it is needed.
Gene name
NQO1 (NAD(P)H quinone dehydrogenase 1)
Location
16q22.1
Protein description
This gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a cytoplasmic 2-electron reductase. Its enzymatic activity prevents the reduction of quinones that lead to production of radical oxygen species that damage DNA.
Gene name
PALB2 (Partner and localizer of BRCA2)
Location
16p12.2
Protein description
This gene encodes a protein that may function in tumor suppression by binding to and co-localizing with BRCA2 protein in nuclear foci, permitting the stable intranuclear localization and accumulation of BRCA2.
Gene name
PTPN11 (Protein tyrosine phosphatase non-receptor type 11)
Location
12q24.13
Protein description
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration.
Gene name
RPS14 (Ribosomal protein S14)
Location
5q33.1
Protein description
This gene encodes a ribosomal protein that is a component of the 40S subunit of ribosomes.
Gene name
RUNX1 (RUNX family transcription factor 1) (AML1)
Location
22q22.12
Protein description
Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene is the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis.
Gene name
SAMD9L (Sterile alpha motif domain containing 9 like)
Location
7q21.2
Protein description
This gene encodes a cytoplasmic protein that acts as a tumor suppressor but also plays a key role in cell proliferation.
Gene name
SRSF2 (Serine and arginine rich splicing factor 2)
Location
17q25.2
Protein description
The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors which constitute part of the spliceosome. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation.
Gene name
TET2 (Tet methylcytosine dioxygenase 2)
Location
4q24
Protein description
The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine and is involved in myelopoiesis.
Gene name
TP53 (Tumor protein p53)
Location
17p13.1
Protein description
This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, and metabolic changes.

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Citation

Mark A Micale

Therapy-Related Hematopoietic Neoplasia

Atlas Genet Cytogenet Oncol Haematol. 2020-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1303/therapy-related-hematopoietic-neoplasia

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