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Molecular diagnostics andrisk assessment inmyeloid malignancies 63

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Table4.4 WHO 2022 classification and ICC 2022 of MDS

WHO ICC

Myelodysplastic neoplasms (MDS) Myelodysplastic syndromes (MDS) MDS with defining genetic abnormalities

MDS with low blasts and isolated 5q deletion (MDS-

(<5%BM; <2% PB)

MDS with low blasts and SF3B1 mutation* (MDS- SF3B1)

(<5%BM; <2% PB)

MDS with biallelic TP53 inactivation (MDS- biTP53) (<20% BM; PB) Myelodysplastic syndrome with mutated TP53 (0–9% BM and PB)

MDS, morphologically defined Myelodysplastic syndrome, not otherwise specified (MDS, NOS)

n.a. MDS, NOS without dysplasia (<5% BM; <2% PB, ≥10% VAF) MDS with low blasts (MDS- LB) (<5% BM; <2% PB) MDS, NOS with single lineage dysplasia (<5% BM; <2% PB)

MDS, hypoplastic** (MDS- h) (<5% BM; <2% PB) n.a. MDS with increased blasts (MDS- IB) MDS- IB1 (5–9% BM; 2–4% PB) Myelodysplastic syndrome with excess blasts (MDS- EB) (5–9%

MDS- IB2 (10–19% BM; 5–19% PB or Auer rods) Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)

MDS with fibrosis (MDS- f) (5–19% BM; 2–19% PB) n.a.

5q)

Myelodysplastic syndrome with del(5q) (<5% BM; <2% PB)

Myelodysplastic syndrome with mutated SF3B1 (<5% BM; <2% PB)

MDS, NOS with multilineage dysplasia (<5% BM; <2% PB)

BM; 2–9% PB*)

(10–19% BM or PB) MDS/AML with mutated TP53 MDS/AML with myelodysplasia- related gene mutations MDS/AML with myelodysplasia- related cytogenetic abnormalities MDS/AML not otherwise specified

Myelodysplastic neoplasms of childhood (<18 years of age) Pediatric and/or germline mutation- associated disorders

Childhood MDS with low blasts (cMDS- LB) (<5% BM; <2% PB) cMDS- LB– Hypocellular cMDS- LB– Not otherwise specified Childhood MDS with increased blasts (cMDS- IB) (5–19% BM;

2–19% PB)

*Detection of ≥15% ring sideroblasts may substitute for SF3B1

mutation. Acceptable related terminology: MDS with low blasts and ring sideroblasts

**By definition, ≤25% bone marrow cellularity, age adjusted

Required blast percentages for diagnosis are displayed in gray

Sources: Adapted from Khoury, J.D., Solary, E., Abla, O. etal. (2022). The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 36(7), 1703–1719 and Arber, D.A., Orazi, A., Hasserjian, R.P. etal. (2022). International consensus classification of myeloid neoplasms and acute leukemias: integrating morphological, clinical, and genomic data. Blood 140(11), 1200–1228.

present, AML with TP53 mutation should be diagnosed according to the ICC.

Overall, there is a clear move toward genetic definitions inboth classifications, but also a recognition that integrated diagnostics is more important than ever before. The differences

*Given their unique biological features and treatment approach,

pediatric (age < 18 years) MDS- EB will continue to include patients with 10–19% blasts

in the classifications allow new research efforts to refine the definitions in the next revision and possibly even a harmonization of the two divergent classification systems. A detailed overview of both classifications and their subgrouping of MDS and AML is provided in Tables4.4 and4.5, respectively.

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64 Molecular Hematology

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Table4.5 WHO 2022 classification and ICC 2022 of AML.

WHO ICC

Acute myeloid leukemia (AML) Acute myeloid leukemia (AML) Acute myeloid leukemia with defining genetic

abnormalities

Acute promyelocytic leukemia with PML::RARA fusion Acute promyelocytic leukemia (APL) with t(15;17)

(q24.1;q21.2)/PML::RARA (≥10%) n.a. APL with other RARA rearrangements (≥10%) Acute myeloid leukemia with RUNX1::RUNX1T1 fusion AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 (≥10%) Acute myeloid leukemia with CBFB::MYH11 fusion AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11 (≥10%) Acute myeloid leukemia with DEK::NUP214 fusion AML with t(6;9)(p22.3;q34.1)/DEK::NUP214 (≥10%) Acute myeloid leukemia with RBM15::MRTFA fusion see below Acute myeloid leukemia with BCR::ABL1 fusion (≥20%) AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 (≥20%) Acute myeloid leukemia with KMT2A rearrangement AML with other KMT2A rearrangements (≥10%) n.a. AML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A (≥10%) Acute myeloid leukemia with MECOM rearrangement AML with other MECOM rearrangements (≥10%) n.a. AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1)

(≥10%) Acute myeloid leukemia with NUP98 rearrangement see below Acute myeloid leukemia with NPM1 mutation AML with mutated NPM1 (≥10%) Acute myeloid leukemia with CEBPA mutation (≥20%) AML with in-

frame bZIP CEBPA mutations (≥10%)

Acute myeloid leukemia, myelodysplasia- related (AML- MR)

(≥20%)

Defining cytogenetic abnormalities AML and MDS/AML with myelodysplasia- related cytogenetic

abnormalities (10–19% MDS/AML; ≥20% AML)

Complex karyotype (≥3 abnormalities) complex karyotype (≥3 unrelated clonal chromosomal abnormalities in the

absence of other class- defining recurring genetic abnormalities) 5q deletion or loss of 5q due to unbalanced translocation del(5q)/t(5q)/ add(5q) Monosomy 7, 7q deletion, or loss of 7q due to unbalanced

translocation 11q deletion n.a. 12p deletion or loss of 12p due to unbalanced translocation del(12p)/t(12p)/add(12p) Monosomy 13 or 13q deletion n.a. 17p deletion or loss of 17p due to unbalanced translocation −17/add(17p) or del(17p) Isochromosome 17q i(17q) idic(X)(q13) idic(X)(q13) clonal abnormalities n.a. +8 n.a. del(20q)

Defining somatic mutations AML and MDS/AML with myelodysplasia- related gene mutations

ASXL1 ASXL1 BCOR BCOR EZH2 EZH2 n.a. RUNX1 SF3B1 SF3B1 SRSF2 SRSF2 STAG2 STAG2 U2AF1 U2AF1 ZRSR2 ZRSR2

−7/del(7q)

(10–19% MDS/AML; ≥20% AML)

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Table4.5 (Continued )

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WHO ICC

Molecular diagnostics andrisk assessment inmyeloid malignancies 65

Acute myeloid leukemia with other defined genetic

alterations(≥20%)

AML with RUNX1T3(CBFA2T3)::GLIS2 AML with inv(16)(p13.3q24.3)/CBFA2T3::GLIS2 n.a. AML with t(16;21)(q24.3;q22.1)/RUNX1::CBFA2T3 AML with KAT6A::CREBBP AML with t(8;16)(p11.2;p13.3)/KAT6A::CREBBP AML with FUS::ERG AML with t(16;21)(p11.2;q22.2)/FUS::ERG AML with MNX1::ETV6 AML with t(7;12)(q36.3;p13.2)/ETV6::MNX1 AML with NPM1::MLF1 AML with t(3;5)(q25.3;q35.1)/NPM1::MLF1 n.a. AML with t(1;3)(p36.3;q21.3)/PRDM16::RPN1 see above AML (megakaryoblastic) with t(1;22)(p13.3;q13.1)/RBM15::MRTFA n.a. AML with t(5;11)(q35.2;p15.4/NUP98::NSD1 n.a. AML with t(11;12)(p15.4;p13.3)/NUP98::KMD5A see above AML with NUP98 and other partners n.a. AML with t(10;11)(p12.3;q14.2)/PICALM::MLLT10

Acute myeloid leukemia, defined by differentiation AML not otherwise specified (NOS) (10–19% (MDS/AML); ≥20% AML) Acute myeloid leukemia with minimal differentiation Acute myeloid leukemia without maturation Acute myeloid leukemia with maturation Acute basophilic leukemia Acute myelomonocytic leukemia Acute monocytic leukemia Acute erythroid leukemia AML and MDS/AML with mutated TP53 (10–19% MDS/AML; ≥20% AML) Acute megakaryoblastic leukemia

Myeloid sarcoma Myeloid sarcoma

AML with other rare recurring translocations (≥10%)

Required blast percentages for diagnosis are displayed in gray

References

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sensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood 140 (11): 1200–1228.

Khoury, J.D., Solary, E., Abla, O. et al. (2022). The 5th edition of the

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Bacher, U., Schnittger, S., Macijewski, K. et al. (2012). Multilineage

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Further reading

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Brandts, C.H., Sargin, B., Rode, M. etal. (2005). Constitutive activation of Akt

by Flt3internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 65: 9643–9650.

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66 Molecular Hematology

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Cancer Genome Atlas Research Network (2013). Genomic and epig-

enomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368: 2059–2074.

Chen, W., Drakos, E., Grammatikakis, I. etal. (2010). mTOR signaling

is activated by FLT3kinase and promotes survival of FLT3acute myeloid leukemia cells. Mol. Cancer 9: 292.

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agement of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129: 424–447.

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management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140: 1345–1377.

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leukemia. N. Engl. J. Med. 373: 1136–1152.

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has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1). Blood 115: 3776–3786.

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tions in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J. Clin. Oncol. 29: 1364–1372.

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ger 1mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood 120: 395–403.

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acute myeloid leukemia in younger adults and its clinical relevance. Blood 127: 29–41.

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negative

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Chapter5

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Molecular basis ofacute

lymphoblastic leukemia

Shunsuke Kimura and Charles G. Mullighan

Department of Pathology, Hematological Malignancies Program, St. Jude Children’s Research Hospital, Memphis, TN, USA

Introduction, 67 B- cell precursor acute lymphoblastic leukemia, 69 High hyperdiploid ALL, 69 Hypodiploid ALL, 71 Intrachromosomal amplification of chromosome 21 (iAMP21), 72

ETV6::RUNX1 and ETV6::RUNX1- like ALL, 73 TCF3-

rearranged ALL (TCF3::PBX1 and TCF3::HLF), 73 KMT2A- rearranged ALL, 74 BCR::ABL1 (Ph+) and Ph- like ALL, 74 DUX4- rearranged ALL, 76 MEF2D- rearranged ALL, 76 ZNF384- rearranged leukemia, 76

Introduction

Survival rates for children with acute lymphoblastic leukemia (ALL) now exceed 90% in high- income countries, but decline with increasing age and cure rates of adult ALL are less than 40%. In addition to minimal/measurable residual disease (MRD, the small number of cancer cells that may remain after treatment) stratified therapy and optimization of supportive care, advances in characterization of the molecular basis of ALL have had an important role in guiding risk stratification and modulation of therapeutic intensity, and have identified new opportunities for precision medicine.

For example, in B- ALL, KMT2A (MLL) rearrangement is considered high risk, whereas less intensive therapy has been applied to cases with ETV6::RUNX1 and high hyperdiploid B-ALL due to their favorable outcomes. However, many newly identified subtypes, which vary by age, are not evident with conventional approaches but are an important determinant of prognosis. Recent high- throughput sequencing technologies (also known as next- generation sequencing that allow generation of very large amounts of sequencing data in

PAX5- driven ALL (PAX5alt and PAX5 P80R), 77

CDX2/UBTF ALL, 77 NUTM1- rearranged ALL, 77

IKZF1N159Y, 78 Other subtypes of B- ALL, 79 T- cell precursor acute lymphoblastic leukemia (T- ALL), 79

TLX1 and TLX3TAL1- and class II basic helix- loop- helix (bHLH)

factor- deregulated T- ALL, 80 Other subtypes of T- ALL, 80 Summary, 80 Further reading, 81

driven T- ALL, 79

a relatively short time) have enabled a comprehensive identification and characterization of these new leukemia subtypes. This includes fusion oncogenes (MEF2D, ZNF384), translocations resulting in oncogene deregulation (DUX4), translocations that redirect the action of enhancers (“enhancer hijacking/retargeting”; BCL11B, CDX2/UBTF), subtypes with similar gene expression profiles to established phenotypes (Ph- like, ETV6::RUNX1- like), and subtypes characterized by single point mutations (PAX5 P80R, IKZF1N159Y, IDH1 R132C, IDH2 R140Q, ZEB2 H1038R) (Figure5.1–5.3).

Sequencing technologies have also characterized the genomic features of T- ALL and acute leukemias of ambiguous lineage (ALAL). However, they are less well integrated into clinical management yet because their genomic features are complex and are difficult to adequately resolve due to the involvement of non- coding regions (the portions of a genome that do not encode proteins) including enhancer hijacking, thus resulting in less consistent association with clinical outcomes.

Detection of specific genomic alterations is also essential for developing precision medicine. One successful example is BCR::ABL1 ALL, whose outcome has markedly improved by

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68 Molecular Hematology

(A)

(B)

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KMT2A

PAX5 P80R

KMT2A-like

Other

BCL2/MYC

PAX5alt

MEF2D

NUTM1

IKZF1 N159Y

CRLF2

non-Ph-like

ETV6::RUNX1

TCF3::PBX1

HLF

Low hypodiploid

Ph-like

iAMP21

CDX2/UBTF

Near haploid

Low hyperdiploid

ETV6:: RUNX1-like

DUX4

ZNF384

ZNF384-like

High hyperdiploid

T cell differentiation

Double negative

(DN)

T-cell lineage

commitment

β-selection

Immature

single-positive

Double positive

(DP)

Positive/negative

-selection

Figure 5.1 Main subtypes of B- and T- ALL. (A) Gene expression profiles of B- ALL based on whole transcriptome sequencing showing tSNE plot of 2004 cases (Source: Adapted from Kimura etal. (2022). Blood. 139 (24): 3519–3531.) by using the top1000most variable genes on the basis of median absolute deviation with a perplexity score of 30. Each dot represents a sample. Major ALL subtypes are highlighted in different colors. (B)T- cell differentiation and T- ALL subtyping describing the differentiation stages of each T- ALL subtype according to the specific genetic alterations leading to aberrant expression of rearranged or mutated genes. Prevalence and prognosis of each subtype are shown. Subtypes are colored according to corresponding normal T- cell differentiation stage: early T- cell precursor (ETP, red and orange), early stages of cortical thymocytes maturation or double positive (DP)/immature single- positive (ISP, green), and late stages of cortical thymocytes maturation or double positive (DP,blue). Abbreviations: T- ALL: T- cell acute lymphoblastic leukemia; T/M MPAL: T/myeloid mixed phenotype acute leukemia; −R: rearranged.

Subtype

Immature

Includes ETP-ALL

LMO2/LYL1

Early T-cell progenitor (ETP)Early corticalLate cortical

NKX2-1

TAL1-RB

TAL1-RA

BCL11B

LMO1

/ISP

HOXA

SPI1

TLX3

TLX1

Alterations Co-legions Prevalence Prognosis

BCL11B-R

(Except BCL11B-TLX3)

LMO1-R LMO2-R RUNX1, FLT3,

Enhancer mutations

HOXA9/10-R

-R

MYB-R

MLLT10-R

SET-NUP214

SP/1-R

TLX3-R

TLX1-R

NKX2-1-R NKX2-5-R

TAL1/TAL2-R

with LMO2-R

Enhancer mutations

FLT3-ITD, WT1 Good

TCF7, NRAS

ETV6, CNOT3, EZH2,

JAK3, STAT5B

NRAS, KRAS

PHF6, CTCF, WT1,

DNM2, RPL5, KDM6A

BCL11B, RB1, CDKN1B

LEF1, RPL10

PTEN, 6q del,

PI3KCD

<5% of T-ALL, AML, and T/M MPAL

(30% of ETP-ALL and T/M MPAL)

<2% of T-ALL

<10% of T-ALL

<25% of T-ALL

<4% of pediatric T-ALL

20–25% Children, <5% Adult

5–10% Children, <30% Adult

<5% of pediatric T-ALL

30–40% of T-ALL

Poor

Intermediate

Very poor

Excellent

Intermediate/Poor

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Molecular basis ofacute lymphoblastic leukemia 69

100%

Children Childhood SR Childhood HR AYA Adult

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Other Ph-like

90%

80%

70%

50%

40%

30%

20%

10%

Figure 5.2 Distribution of B- ALL subtypes within age group. Frequency of each B- ALL subtype (Source: Adapted from Gu etal. (2019).

Nat.Genet. 51 (2): 296–307) are shown in children (1191 cases, −15 years), adolescents and young adults (AYA, 419 cases, 16–39 years), andadults (378 cases, 40– years). Standard risk (SR) and high risk (HR) are defined according to NCI criteria.

BCR::ABL1

BCL2/MYC CRLF2 non-Ph-like CDX2/UBTF ZEB2/CEBPE IKZF1 N159Y PAX5 P80R PAX5alt NUTM1 HLF MEF2D ZNF384-like ZNF384 DUX4

TCF3::PBX1

KMT2A-like KMT2A

ETV6::RUNX1-like ETV6::RUNX1

Near haploid Low hypodiploid iAMP21 Low hyperdiploid High hyperdiploid

Aneuploidies Transcription factor driven Kinase driven

adding tyrosine kinase inhibitors (TKIs). Furthermore, in patients with alterations in JAK–STAT signaling or ABL- class fusions, several FDA- approved TKIs are currently tested in frontline studies. In addition to somatic alterations that define genomic subtypes and targeted approaches, germline variants associated with ALL risk and somatic alterations related to disease relapse have also been widely analyzed and may potentially improve precision medicine (also known as personalized medicine involves tailoring medical decisions and interventions to the specific characteristics of each patient).

Thus, high- throughput sequencing technologies are optimal for diagnosis and precision medicine for ALL. While not yet generally available, the clinical use of genome and transcriptome sequencing is becoming increasingly adopted. Alternative, focused approaches may also be used to identify many subtypes, including flow cytometry (e.g. for rearrangement and deregulation of CRLF2), fluorescence in-situ hybridization (FISH, for rearrangements and fusion events), and focused, capture-

based sequencing approaches that can detect many mutations and rearrangements (e.g. Archer FUSIONPlex Pan- Heme or Foundation Medicine). Moreover, whole transcriptome sequencing as a single platform approach can detect most subtypes of B- ALL robustly, and several workflows for automated analysis of data have been reported. This chapter describes the updated genomic landscape of B- ALL and T- ALL, focusing on genomic characterization and the implications of the therapeutic strategies.

B- cell precursor acute lymphoblastic leukemia

Significant advancements in recent genome analysis have led to the comprehensive elucidation of genomic abnormalities in B- ALL and have revised the classification of this disease. Subtypes of B- ALL are primarily classified into the following four categories according to nature of driver alteration: (1) chromosomal abnormalities (aneuploidy, iAMP21), (2)transcription factor (TF) or oncogene- driven by chimeric fusion oncoprotein (ETV6::RUNX1, TCF3::PBX1, KMT2A- , HLF-

, ZNF384- , NUTM1- , MEF2D- rearranged), rearrangements (DUX4- , MYC- rearranged, CDX2/UBTF), or point mutations (PAX5 P80R, IKZF1N1559Y), (3) kinase- driven (BCR::ABL1, Ph- like), and (4) other provisional entities (phenocopies of several known subtypes, PAX5alt, ZEB2/ IGH::CEBPE). Each abnormality is described in the following sections.

High hyperdiploid ALL

High hyperdiploid ALL is one of the most common genetic subtypes of pediatric leukemia, accounting for 25–30% of B- ALL in children with a median age at diagnosis of three to five years, but less than 5% in adult ALL (Figure5.2). The definition of high hyperdiploid ALL is either of 51–67

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Alteration Subtype Driver Peak Prevalence Tools for Diagnosis

Chromosome number ≥ 51

Karyotyping, FISH, SNP array, WGS

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Chromosome number 31–39

Chromosome number 24–30

Intrachromosomal amp

of chromosome 21

ETV6::RUNX1 fusion

KMT2A-rearrangements

DUX4-rearrangements

MEF2D-rearrangements

ZNF384-rearrangements

NUTM1-rearrangements

HLF1-rearrangements

BCL2-R, MYC-R, BCL6-R

UBTF::ATXN7L3 fusion

IGH::CEBP/ ZEB2 H1038R

without BCR::ABL1

GEP of ETV6::RUNX1

without the fusion

TCF3::PBX1 fusion

BCR::ABL1 fusion

PAX5 P80R

IKZF1 N159Y

GEP of PAX5alt

GEP of Ph

GEP of KMT2A-R

GEP of ZNF384-R

Yes

Hyperdiploid None Children (25%) Karyotyping, WGS

Yes

Low hypodiploid

Near haploid

iAMP21

ETV6::RUNX1

KMT2A

TCF3::PBX1

BCR::ABL1

DUX4

MEF2D

ZNF384

NUTM1

HLF

BCL2/MYC

CDX2/UBTF

PAX5 P80R

IKZF1 N159Y

ZEB2/CEBP

PAX5alt

Ph-like

ETV6-RUNX1-

KMT2A-like

ZNF384-like

None

± CRLF2-R

ETV6::RUNX1

KMT2A-R

TCF3::PBX1

BCR::ABL1

DUX4-R

MEF2D-R

ZNF384-R

NUTM1-R

TCF3::HLF TCF4::HLF

BCL2-R/MYC-R BCL6-R

UBTF::ATXN7L3

13q12.2 del

None

IGH-CEBP

± PAX5-R ± CRLF2-R

CRLF2, ABL 1/2 CSFR1, PDGFRA/B, LYN, EPOR, JAK2, TYK2, many

± ETV6-R, ± IKZF1-R, ± CRLF2-R

± HOXA-R

Adults (10–15%)

<3% in all ages

<3% in children

and AYA

Children (25%)

Infants (80%) and

adults (25%)

Children (8%)

Adult (40–50%)

AYA (8%)

AYA (7%)

AYA (5%)

Children (1%)

<1% in all ages

AYA and adults (3%)

AYA and Adults female (1–2%)

Adults (4%)

<1% in all ages

AYA/Adults (1%)

Children (10%)

AYA (25–30%)

Children (3%)

Children/AYA (<1%)

AYA/Adule (<1%)

Karyotyping, WGS

FISH, RT-PCR, WTS, WGS

RT-PCR, WTS, WGS

FISH, RT-PCR, WTS, WGS

WTS, WGS

FISH, RT-PCR, WTS, WGS

WTS, WGS

WTS

B-other

Figure 5.3 The schematic algorithm for B- ALL subtyping and tools for diagnosis (Source: Adapted from Paietta etal. (2021). Blood 38 (11): 948–958.). This figure describes how to define each B- ALL subtype by using karyotyping, whole genome sequencing (WGS), whole transcriptome sequencing (WTS), fluorescence in- situ hybridization (FISH), and reverse transcription- polymerase chain reaction (RT- PCR), and SNP array. Each subtype is colored according to defining genetic events: gross chromosomal abnormalities (purple), transcription factor driven (blue), kinase driven (blue), and kinase driven (orange).

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Molecular basis ofacute lymphoblastic leukemia 71

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chromosomes or DNA index ≥1.16, though these are imperfectly correlated. Extra chromosomes are typically characterized by a non- random chromosomal gains, most commonly X, 4, 6, 10, 14, 17, 18, and 21. Mechanistically, impaired condensin complex function leads to chromosome hypocondensation and mislocalization of chromosome passenger complex, including Aurora B kinase (AURKB) and Survivin in early mitosis. Impaired AURKB activity induces defects in the spindle assembly checkpoint and chromosome misalignments at the metaphase plate, leading to robust chromosomesegregation defects and nonmodal karyotypes.

In general, high hyperdiploid ALL is associated with favorable outcomes, but several factors for predicting outcomes are reported; triple trisomy (gain of additional chromosomes of 4, 10, and 17), +17 and +18, +17 or +18without +5/+20 for favorable outcomes, and SETD2 alterations for higher relapse rate (Table5.1). Due to the lack of an established consensus for the definition of high hyperdiploid ALL and prognostic factors, the criteria used to define the favorable prognostic subgroup among high hyperdiploid ALL vary among clinical trials. For example, the Children’s Oncology Group adopted double (+4, +10) or triple trisomy (+4, +10, +17) as a surrogate marker for high hyperdiploidy. However, this subgroup represents only two- thirds of high hyperdiploid cases. Genomically, most cases harbor the receptor tyrosine kinase (RTK)- Ras pathway (KRAS, NRAS, FLT3,

PTPN11) and histone modifiers (CREBBP, WHSC1, SETD2). CREBBP alterations are enriched in the histone acetyltrans-

ferase domain and reported to be selected during the disease evolution.

Importantly, mutational signature (patterns of specific types of mutations at particular DNA sequence positions) related to ultraviolet (UV) is enriched in high hyperdiploid ALL.

These mutations differ from mutations caused by other sources of radiation, such as ionizing radiation, in terms of the types of alterations observed in the DNA sequence. UVinduced mutations are most commonly found on only one of three triploid chromosomes, indicating copy number gains precede UV exposure. The most common scenario of generation of aneuploidy is an early synchronous pattern observed in ~80% of cases, in which chromosomal gains precede the acquisition of point mutations. Less commonly, a late synchronous pattern (mutations occur before copy gains) and an asynchronous gain pattern with one late whole/ arm chromosomal gains after most copy gains. This is consistent with the high incidence of ALL in European ancestry than in African descent and the fact that hyperdiploidy is often detectable at birth.

The gene expression profile of high hyperdiploid ALL (Figure5.1A) is quite similar to that of near haploid ALL in part due to increased relative dosage of chromosomes 10, 14, 18, and 21, which are frequently gained in high hyperdiploid ALL but are often kept intact in near haploid. They both commonly show frequent alterations in CREBBP and Ras

pathway genes but affect different genes; NRAS, KRAS, and PTPN11 in high hyperdiploid ALL, and NF1 deletions in near haploid ALL.

Hypodiploid ALL

Hypodiploid ALL is an uncommon subtype of B- ALL with 44 chromosomes or fewer and subdivided into two main distinct subtypes based on the severity of aneuploidy: low hypodiploid ALL (30–39 chromosomes or DNA index

0.65–0.82) and near haploid ALL (24–29 chromosomes or DNA index below 0.65). High hypodiploid ALL (40–44 chromosomes) is heterogeneous and not a distinct subtype, which differs from low hypodiploid ALL and near haploid ALL in their genomic alterations, expression profiles, and outcomes. Both low hypodiploid and near haploid ALL are associated with unfavorable prognosis despite the improvement of outcomes by MRD- stratified therapy, except for those who achieved MRD- negative status at the end of induction (EOI) therapy (Table5.1). The difference in CD10 positivity (positive for near haploid and positive/negative for low hypodiploid ALL) might associate with cell of origin, pro- B, or earlier stage in low hypodiploid ALL. Like high hyperdiploid ALL, chromosome loss in hypodiploid ALL is non- random with frequent loss of chromosomes 3, 7, 9, 15, 16 and 17. In contrast, chromosome 21 is never lost. In near haploid ALL, retained chromosomes (i.e. two copy, disomic chromosomes) include chromosomes 8, 10, 14, 18, 21, and X/Y, similar to gained chromosomes in high hyperdiploid ALL. Correspondingly, the gene expression profiles of near haploid and high hyperdiploid ALL are similar (Figure5.1A).

Duplication of the aneuploid genome is a frequent phenomenon in hypodiploid ALL, known as masked hypodiploidy, and may be mistaken for high hyperdiploid ALL. This chromosomal doubling is considered to occur via endoreduplication and is found only at diagnosis. The difference in gained chromosomes can distinguish masked hypodiploid cases: diploid (normal, 2 chromosomes) and tetraploid (4 chromosomes) in masked hypodiploidy, instead, a mixture of triploid (3 chromosomes) and some tetraploid (4 chromosomes on chromosomes 21, X) in high hyperdiploidy. In addition, single nucleotide polymorphism (SNP) array or genomic sequencing can easily identify masked hypodiploidy by detecting loss of heterozygosity (LOH) in most chromosomes (Figure5.3).

Almost all low alterations affecting the DNA- binding domain, half of which are constitutional in children, suggesting possible LiFraumeni syndrome. In contrast, low hypodiploid ALL is more frequent in adult ALL and almost all adult cases have somatic biallelic TP53 inactivation. However, TP53 mutations were detected in 34% of remission samples of adult cases suggesting preexisting TP53 mutant clonal hematopoiesis. Other frequent alterations include IKZF2, RB1, and

hypodiploid ALL harbor biallelic TP53

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72 Molecular Hematology

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Table 5.1 Novel or potential therapeutic approaches foreach B- ALL subtype

Subtype Prevalence Risk Novel or potential approaches

Hyperdiploid 20–25% Children, 2–5% Adult Good Identify high-

chromosome gains

Hypodiploid –4% Children, 10–15% Adult Poor PI3K and BCL2inhibitors, Src kinase inhibitors

(dasatinib, ponatinib) for PAG1 deletion

iAMP21 1–2% Children, −1% Adult Intermediate No standard risk treatment, JAK/STAT

inhibitors, check germline alterations (Robertsonian, ring chr 21)

ETV6::RUNX1 15–20% Children, −2% Adult Good Identify high- risk cases (TBL1XR1 mutations) ETV6::RUNX1- like −5% Children, −1% Adult Intermediate Check germline ETV6/PAX5 alterations TCF3::PBX1 5–6% Children, 1% Adult Intermediate Src kinase inhibitors, ROR1inhibitors TCF3::HLF −1% Children, −1% Adult Poor Aurora A kinase inhibitors, BCL2inhibitors, Src

kinase inhibitors, EP300inhibitors

KMT2A- rearranged Frequent in infant ALL, 5% Children,

−20% Adult BCR::ABL1 (Ph+) −5% Children, 15% Adult Poor Kinase inhibitors, retinoids, FAK inhibitors Ph-

like 10–15% Children, 20% Adult Poor Kinase inhibitors, TRK inhibitors, FLT3inhibitors,

DUX4- rearranged 5% Children, −5% Adult Good Potentially reduce intensity MEF2D- rearranged 2–4% Children, 1% Adult Intermediate HDAC inhibitors, Src kinase inhibitors,

ZNF384- rearranged 2–4% Children, 1–2% Adult Intermediate FLT3inhibitors

PAX5- driven (PAX5 alt/P80R)

CDX2/UBTF 2–4% Female AYA, Rare in Children Poor Unknown NUTM1- rearranged Infant ALL Good Bromodomain inhibitors

IKZF1N159Y −1% Children, −1% Adult Intermediate Retinoids, FAK inhibitors, check germline

BCL2/MYC −1% Children, 1–3% Adult Poor Unknown Hyper- mutation Relapse Checkpoint blockade

5–10% Children, 10–15% Adult Intermediate Unknown

Poor DOT1L inhibitors, Menin inhibitors, targeting

CD72

JAK/STAT inhibitors, immune therapy

bortezomib

IKZF1N159 alterations

risk cases by the combination of

CDKN2A/B. Near haploid ALL is almost restricted to children and genomically characterized by alterations in RTKRas pathway (particularly NF1), histone modifiers (CREBBP), and IKZF3. In addition, PAG1 deletions are found in 10% of nearSrc- family kinases that may be amenable to targeted therapy with SRC inhibitors such as dasatinib. The efficacy of PI3K and BCL2inhibitors and the synergistic effect of BCL2 and cyclin- dependent kinase (CDK) inhibitors have been shown in preclinical studies and can be promising targets in hypodiploid ALL (Table5.1).

Intrachromosomal amplification of chromosome 21 (iAMP21)

B- ALL with iAMP21 accounts for approximately 1–2% of pediatric ALL associated with older children (median age of nine years) but is rare in adults, and a low white blood cell

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haploid, suggesting deregulation of

count (Figure 5.2). The current definition of iAMP21 by FISH is (1) greater than or equal to three extra copies of RUNX1 gene on a single abnormal chromosome 21, or (2) greater than or equal to five copies of RUNX1 gene region per interphase cell. FISH probes for detecting ETV6::RUNX1 fusion are clinically used to identify iAMP21 because RUNX1 is in the common region of chromosome 21amplification, which maps approximately 40

Mb from TIAM1 to HMGN1 and includes several genes implicated in the pathogenesis of B- ALL (CHAF1B, DYRK1A, ERG, HMGN1, RUNX1). However, approximately 9% of iAMP21 fails to meet the definition of iAMP21 by FISH and requires other methods, including chromosomal or SNP microarray and whole genome sequencing for identification (Figure5.3). The accurate detection of iAMP21 is essential, considering that patients with iAMP21 showed poor outcomes with standardrisk treatment but could overcome with intensive high- risk treatment. Mechanistically, iAMP21 is induced by the results of breakage- fusion- bridge cycles and chromothripsis. The

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