**4. Differential diagnosis**

#### **4.1** *KMT2A***-rearranged AML masquerading as JMML**

Unlike in AML, the bone marrow in patients with JMML demonstrates no blockage of differentiation of myeloid elements. Rather, as is seen in chronic myeloid leukemia (CML), the bone marrow in JMML displays myeloid hyperplasia with increased production of monocytic cells along the full spectrum of differentiation, including blast forms, promonocytes, monocytes, and macrophages. The marrow blast count may be slightly elevated but in classic JMML it does not reach the counts seen in AML. Nevertheless, differentiating JMML from AML is nearly impossible on clinical grounds alone as significant hepatosplenomegaly and respiratory failure can occur in both. Moreover, blood counts and hematologic features may mimic AML. This especially holds true for infants with the lysine methyltransferase 2A (*KMT2A*) rearrangements who occasionally present with hepatosplenomegaly and low blast count resembling JMML [5]. A puzzling interface between *KMT2A*-rearranged AML and JMML therefore exists. Recent reports have validated the close mimicry between *KMT2A*rearranged AML and JMML [6]. Unless unveiled by cytogenetics, JMML can conceal the clinical diagnosis of *KMT2A*-rearranged AML. Age of susceptibility (infancy or early childhood) and abnormal monocytosis have blurred the line between these distinct entities. Specifically, JMML may mimic AML with t(9;11). t(9;11) is the most frequent molecular subtype involving the *KMT2A* gene (*KMT2A-MLLT3*) in AML. t(9;11)-positive AML/JMML overlap was well-characterized in the medical literature [7]. Both conditions have increased immature monocytes and blasts. I reported a 14-month-old girl with t(9;11)-positive AML who died as she received JMML-directed therapy. The clinical picture, peripheral smear and the suboptimal blast count of only 10% had stealthily impersonated JMML [8].

Chromosomal rearrangements involving the *KMT2A* gene do not exist in the genomic landscape of JMML. KMT2A gene rearrangements are common genetic mutations in pediatric AML with an incidence of 15–25% (50–60% in children younger than two years). However, both KMT2A-rearranged AML and JMML share common morphologic features. *KMT2A*-rearranged AML is usually AML M4 or M5, and both are characterized by increased numbers of monoblasts or abnormal

monocytes. JMML morphologically resemble AML M4 and distinction must be made based on accurate blast and promonocyte counts.

Differentiating AML from JMML is vital for survival. Chemotherapy regimens for JMML are mainly cytoreductive as a bridge to hematopoietic stem cell transplantation (HSCT) rather than curative as for AML. Therefore, any delay in establishing the correct diagnosis and/or administration of wrong treatment can be lethal. Molecular diagnosis has become the mainstay to distinguish between AML and JMML. Cytogenetics and FISH should be immediately performed to detect *KMT2A* gene rearrangements in every suspicious case.

#### **4.2 JMML masquerading as RALD**

JMML is closely related to RAS-associated autoimmune leukoproliferative disorder (RALD) [9]. RALD is a non-malignant, non-infectious leukoproliferative disease that resembles the autoimmune lymphoproliferative syndrome (ALPS) caused by mutations affecting the FAS/FASL pathway.

Similar to patients with ALPS, RALD patients present with lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, and autoimmunity. However, RALD was separated from ALPS as:


RALD is a RAS-associated somatic disorder characterized by myelomonocytic and lymphoid hyperplasia that shares identical somatic *KRAS* or *NRAS* mutations found in up to 25% of JMML patients. It is thought that RAS activation itself can alter selection patterns of autoreactive B cells and antibody production leading to autoimmune manifestations. Overlap features of both JMML and RALD include:


Distinguishing RALD from JMML can be impossible on clinical grounds alone. However, this distinction has an important prognostic value as RALD is characterized by an indolent clinical course whereas JMML can be fatal if left untreated. The most definitive diagnostic distinction between RALD and JMML occurs in the

**19**

*Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of* KMT2A*-Rearranged Acute…*

setting of a cytogenetic abnormality (eg, monosomy 7), which excludes RALD and favors a malignant process. However, normal bone marrow cytogenetics has been

JMML/RALD overlap can lead to inappropriate treatment decisions. In some patients, RALD was misdiagnosed as JMML and vice versa. It is the author's experience that a patient with KRAS-mutated JMML was misdiagnosed as RALD for many weeks until he developed full -blown JMML. It is noteworthy that RALD can occur as the initial presentation and transform to JMML several years later. Indeed, JMML/RALD represents a continuum of two different phenotypes of the same disorder. Although both RALD and JMML share common RAS mutations, the transition from RALD to JMML is caused by additional genetic or epigenetic events. Therefore, patients with RALD should be very closely monitored for acquisition of additional dysplastic, molecular, or clonal karyotypic abnormalties that may herald

JMML can mimic myeloproliferative malignancies with receptor tyrosine kinase translocations. Identification of these cases is crucial, because patients may benefit

cytomegalovirus (CMV). Occasionally, patients with JMML may present with these viral infections in addition to their underlying hematologic malignancy. Differentiation between CMV-related disease and JMML in infants excreting CMV is sometimes difficult, because clinical and laboratory findings of CMV

• Viral infections such as human herpes virus-6 (HHV-6), parvovirus, or

• Wiskott Aldrich syndrome: need to be considered in male infants.

• Infantile malignant osteopetrosis (IMO): can mimic all clinical and hemato-

• Autoimmune diseases, including rheumatoid arthritis and systemic lupus

JMML is an oncogenic RAS mutant cancer where approximately 90% of patients

carry either somatic or germline gain of function mutations in *PTPN11, KRAS, NRAS, CBL, or NF1* genes that lead to constitutive activation of the RAS signaling pathway (**Figure 3**). The RAS signaling pathway is a component of multi-step signal transduction pathway that controls the cellular proliferation, differentiation,

**4.3 JMML masquerading as myeloproliferative neoplasms (MPNs)**

from receptor tyrosine kinase–targeted inhibitors.

**4.4 Nonmalignant disorders mimicking JMML**

infection can overlap with those of JMML.

• Hemophagoytic lymphohistiocytosis (HLH).

**5.1 The central role of the RAS signaling pathway**

• Leukocyte adhesion deficiency variants.

logical features of JMML.

erythematosus.

**5. Genomics**

*DOI: http://dx.doi.org/10.5772/intechopen.94537*

reported in around 65% of JMML patients.

malignant transformation [10].

*Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of* KMT2A*-Rearranged Acute… DOI: http://dx.doi.org/10.5772/intechopen.94537*

setting of a cytogenetic abnormality (eg, monosomy 7), which excludes RALD and favors a malignant process. However, normal bone marrow cytogenetics has been reported in around 65% of JMML patients.

JMML/RALD overlap can lead to inappropriate treatment decisions. In some patients, RALD was misdiagnosed as JMML and vice versa. It is the author's experience that a patient with KRAS-mutated JMML was misdiagnosed as RALD for many weeks until he developed full -blown JMML. It is noteworthy that RALD can occur as the initial presentation and transform to JMML several years later. Indeed, JMML/RALD represents a continuum of two different phenotypes of the same disorder. Although both RALD and JMML share common RAS mutations, the transition from RALD to JMML is caused by additional genetic or epigenetic events. Therefore, patients with RALD should be very closely monitored for acquisition of additional dysplastic, molecular, or clonal karyotypic abnormalties that may herald malignant transformation [10].

### **4.3 JMML masquerading as myeloproliferative neoplasms (MPNs)**

JMML can mimic myeloproliferative malignancies with receptor tyrosine kinase translocations. Identification of these cases is crucial, because patients may benefit from receptor tyrosine kinase–targeted inhibitors.

#### **4.4 Nonmalignant disorders mimicking JMML**

